Ijcp may 2013 by IJCP

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Volume 23, Number 12

May 2013, Pages 781-880

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yy American Family Physician yy Cardiology yy Dentistry yy Diabetology yy Gastroenterology yy Internal Medicine yy Obstetrics and Gynecology yy Orthopedics yy Pediatrics

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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

Volume 23, Number 12, May 2013 from the desk of group editor-in-chief

785 15 Ways to Reduce or Stop Drinking

American Family Physician

787 Practice Guidelines Cardiology

Padma Shri and Dr BC Roy National Awardee

Dr KK Aggarwal Group Editor-in-Chief Dr Veena Aggarwal MD, Group Executive Editor

791 Higher Prevalence Rate of CHD in ‘Apple Type of Obesity’ Cases as Compared to ‘Pear Type Obesity’ Cases

Case Reports and Review of Literature

IJCP Editorial Board 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 Dentistry Dr KMK Masthan Dr Rajesh Chandna Gastroenterology Dr Ajay Kumar Dermatology Dr Hasmukh J Shroff Nephrology Dr Georgi Abraham Neurology Dr V Nagarajan

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

Ibraheem Khan, GN Saxena, Prakash Keshwani, Swati Srivastava, Sher Singh, Gunjan Sharma

critical care

798 Anaphylactic Shock: A Rare Presentation of Phenytoin Drug Reaction

Amit D Bhatt, Anjali N Joshi, AP Jain

799 Anaphylaxis to IV Atropine: A Case Report DA Hiremath

Dentistry

801 Gingival Depigmentation

Sharmila Verma, Meera Gohil, Vandana Rathwa

Diabetology

804 Tuberous Xanthoma in Diabetes Mellitus: A Case Report

Sonia Jain, AP Jain

ENT

806 Scalpel Cautery Adenotonsillectomy Done in a Case of Crouzon’s Syndrome

Sudhir M Naik, Sarika S Naik

Gastroenterology

814 Endoscopic Diagnosis, Screening and Surveillance and Treatment of Barrett’s Esophagus: An Overview

Praveen Kumar Yadav, Teng Fei Chen, Zhanju Liu

Infectious Disease

823 Study of Antioxidant Enzymes, MDA and Lipid Profile in Cerebral Malaria

Journal of Applied Medicine & Surgery Dr SM Rajendran, Dr Jayakar Thomas

OP Patidar

795 Irreversible Thyrotoxic Dilated Cardiomyopathy:

Obstetrics and Gynaecology Dr Alka Kriplani Dr Thankam Verma, Dr Kamala Selvaraj

KK Aggarwal

A Tyagi, R Tyagi, R Vekariya, A Ahuja

Internal Medicine

827 Prevalence Study of Vitamin D Deficiency and to Evaluate the Efficacy of Vitamin D3 Granules 60,000 IU Supplementation in Vitamin D Deficient Apparently Healthy Adults

Pravina Shah, Sudhindra Kulkarni, S Narayani, Dhara Sureka, Supriya Dutta, Ankita S Vipat, Qayum Mukaddam, Kamlesh Patel, Sachin Suryawanshi, Manoj Naik, Manoj Prabhu

833 A Rare Presentation of Osler-Weber-Rendu Disease as Severe Anemia

Kailash Chandra Nayak, Ashish Gupta, Varun K, Ashwani K Vyas, Surendra Kumar, Parul Prakash

Neurology

835 Multiple Myeloma Presenting as Acute Hemiplegia due to Space Occupying Lesion: A Case Report

Shweta Sahai, Atul Sahai

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

837 Uterovaginal Prolapse with Giant Vesical Calculus: A Rare Case Report

Shashidhar B, Krishna Shetty

840 Ovarian Fibrothecoma with Extensive Cystic Degeneration: Two Case Reports Suprabha Sharma, R Bansal, Sanjay Upreti, Anjali Khare, Sangeeta Sharma, Deepti Agarwal

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Orthopedics

842 Osteoporosis: Current Management Guidelines

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.

Harmanjit Singh, Manoj Goyal, Jasbir Singh

Pulmonology

851 Pulmonary Alveolar Microlithiasis: A Clinicoradiological Dissociation

Debaprasad Chakrabarti, Prabhat Debbarma, Amrit Kumar Bhattacharyya

Pediatrics

853 Amniotic Fluid Lamellar Body Count as a Predictor of

Editorial Policies

Fetal Lung Maturity

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Sunanda Kulkarni, Jayamma

Radiology

856 Ruptured Pulmonary Hydatid Cyst: The Camalote Sign

Manjot Kaur, Rakendra Singh

Surgery

859 Gastric Rupture Following Blunt Trauma Abdomen: A Case Report

Ritesh Maheshwari, Ashutosh Sayana, Pankaj Mahesh

Medifinance

861 Need for a Will or Power of Attorney Medilaw

864 What are the Legal Aspects of Over-the-counter Sale of Allopathic Medicines?

MC Gupta

eMedinewS Inspiration

869 A Sweet Lesson on Patience

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.

MC Gupta

Confederation of Medical Associations in Asia and Oceania

871 Be Human Stop Child Abuse Around the Globe

872 News and Views

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from the desk of group editor-in-chief Dr KK Aggarwal

Padma Shri and Dr BC Roy National Awardee Sr. Physician and Cardiologist, Moolchand Medcity, New Delhi President, Heart Care Foundation of India Group Editor-in-Chief, IJCP Group and eMedinewS National Vice President, Elect, IMA Chairman Ethical Committee, Delhi Medical Council Director, IMA AKN Sinha Institute (08-09) Hony. Finance Secretary, IMA (07-08) Chairman, IMA AMS (06-07) President, Delhi Medical Association (05-06) emedinews@gmail.com http://twitter.com/DrKKAggarwal Krishan Kumar Aggarwal (Facebook)

15 Ways to Reduce or Stop Drinking

f you are dependent on alcohol, or have other medical or mental health problems you should stop drinking completely. Reduction of heavy drinking may be a more acceptable goal for some patients who lack readiness to quit drinking.

The frequency of heavy drinking (>5 drinks/day for men and 4 for women) has the highest correlation with negative life consequences such as impaired driving, interpersonal problems and injuries. You need to cut down if in the past one year you have taken one or more times, >5 drinks in a day (4 drinks for women). This positive response to a single question “How many times in the past year have you had X or more drinks in a day?”, where X is five for men and 4 for women, is recommended for use by the National Institute on Alcohol Abuse and Alcoholism. The sensitivity and specificity of this question is 81.8 and 79.3%, respectively. One can also know the dependence of alcohol by using the CAGE questionnaire.

ÂÂ

Have you ever felt the need to Cut down on drinking?

ÂÂ

Have you ever felt Annoyed by criticism of your drinking?

ÂÂ

Have you ever had Guilty feelings about your drinking?

ÂÂ

Do you ever take a morning Eye opener (a drink first thing in the morning to steady your nerves or get rid of a hangover)?

One positive response to any question suggests need for closer assessment; two positive responses are seen in the majority of patients with alcoholism. Two positive responses have a sensitivity of 77% and specificity of 80% in patients with alcohol dependence. Over 80% of nonalcoholic patients have a negative response to all four questions and virtually none has a positive response to >2 questions. National Institute on Alcohol Abuse and Alcoholism suggests the following for stopping or reducing alcohol: 1. Put it in writing why you want to reduce or stop: Write what you want to achieve, for example, will feel healthier; will sleep better, will improve my relationships. 2. Write confessions: Learn and practice various confession exercises. This will help you take care of inner guilt, which may be the precipitating factor. 3. Set a drinking limit: Those who are cutting back should set a limit as per their health. Most healthy people should limit to <40 ml in one hour, 80 ml in one day and <240 ml in a week. Women should take less than half of this amount. 4. Keep a diary of your drinking: For initial 3-4 weeks, keep track of every drink. Note the situations you are most likely to drink. Give each situation a rating out of 10. Try avoiding those situations for the next few weeks.

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from the desk of group editor-in-chief 5. Don’t keep alcohol within your reach: Remove alcohol from your living place. This can help limit drinking. 6. Eat your drink: Drinking slowly can help. Sip and do not gulp. Sip soda, water or juice after each drink. This is called Mindful drinking. If you are aware of your drinking, you will cut back on it. Otherwise, you will drink more. 7. Never drink on an empty stomach. 8. Keep weekly one or two spiritual fast/s. This will allow alcohol-free days. Decide not to drink a day or two each week. 9. Observe spiritual retreats: Observing spiritual retreats (Navratri by Hindus, Ramzan by Muslims and Easter by Christians) with no drinking can help. Or try abstaining for a week or a month to see your commitment to not drinking. 10. Become a tortoise: Learn to withdraw yourself from all stimuli, which can force you to drink. 11. Watch for peer pressure: Learn to say no. Do not drink just because others are, and you shouldn’t feel obligated to accept every drink you’re offered. Stay away from people who encourage you to drink. 12. Keep busy: Take a walk, play sports, go out to eat or catch a movie. When you’re at home, pick up a new hobby or revisit an old one. Painting, board games, playing a musical instrument, woodworking - these and other activities are great alternatives to drinking. 13. Ask for support: Let friends and family members know that you need their support. 14. Guard against triggers: Stay away from people and places that make you want to drink. In Yoga it is called Pratahyara and means staying away from the external stimuli. Lust cannot be removed by staying in a lustful atmosphere. 15. Be persistent: Most people who successfully cut down or stop drinking altogether do so only after several attempts. ■■■■

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American Family Physician

Practice Guidelines

Guidelines for the Use of Opioid Therapy in Patients with Chronic Noncancer Pain The use of opioid therapy for chronic non-cancer pain has increased substantially. Chronic opioid therapy is controversial, however, because of the potential for adverse effects and abuse. The American Pain Society and American Academy of Pain Medicine recently released a guideline for the use of opioids in patients with chronic noncancer pain. The multidisciplinary panel of experts graded the recommendations as strong or weak. A strong recommendation indicates that the benefits clearly outweigh the risks, whereas a weak recommendation indicates a closer balance of benefits to risks or weaker evidence. Decisions to follow weak recommendations should consider individual clinical circumstance, as well as patient preferences and values. The quality of evidence for each recommendation is graded as high, moderate, or low, depending on type, size, and number of studies; strength of associations or effects; and consistency of results among studies.

Recommendations Patient selection and risk stratification A history, physical examination, and appropriate testing should be performed before the initiation of therapy; benefits versus risks should be assessed before and during therapy. A trial of opioid therapy may be considered if pain is moderate or severe and affects the patientâ&#x20AC;&#x2122;s quality of life, and if potential therapeutic benefits are likely to outweigh potential harms (Grade: strong recommendation, low-quality evidence). Proper patient selection using benefit-to-risk assessment is crucial. Risk stratification should evaluate the potential for opioid abuse and risk of adverse effects. Reliable evidence supporting methods of predicting the benefits of chronic opioid therapy is limited. However, randomized trials show that opioid therapy is most beneficial in patients with moderate to severe pain who have not benefited from nonopioid therapy. Useful risk stratification tools are listed in Table 1. Patients with poorly defined pain conditions, a likely somatoform disorder, or unresolved compensation or legal issues may be less likely to benefit from therapy.

Table 1. Assessment Tools for Opioid Therapy in Patients with Chronic Noncancer Pain Risk assessment tools Screener and Opioid Assessment for Patients with Pain* Opioid Risk Tool Diagnosis, Intractability, Risk, Efficacy Score Monitoring tools Pain Assessment and Documentation Tool Current Opioid Misuse Measure* Note: Tools are available in appendices of original article at http:// www.painmed.org/pdf/noncancer_opioid_guidelines.pdf. *Available for purchase at http://www.painedu.com.

Informed consent and opioid management plans Informed consent should be obtained from patients before the initiation of therapy, and an ongoing discussion should include goals, expectations, potential risks, and alternative therapies (Grade: strong recommendation, low-quality evidence). Physicians may consider creating a written plan (Grade: weak recommendation, low-quality evidence). Physicians and patients should discuss the risks and benefits of chronic opioid therapy before treatment and periodically during treatment. An informed consent process assists patients in making appropriate decisions that are consistent with their preferences and values. It is important for physicians to discuss the management plan with patients on an ongoing basis so that patients clearly understand the goals of treatment and have realistic expectations of treatment outcomes. A written plan can be helpful, especially in patients with a higher risk of abuse. Initiation and titration of therapy Initial treatment should be regarded as a therapeutic trial to determine whether chronic opioid therapy is appropriate. Opioid selection, initial dosing, and titration should be individualized based on the patientâ&#x20AC;&#x2122;s health status, previous opioid use, therapeutic goals, and risk of adverse effects (Grade: strong recommendation, low-quality evidence). An initial therapeutic trial should be administered for several weeks to months, guiding the decision to proceed

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American Family Physician with chronic therapy. Dosing is individualized and usually determined by incremental dosage escalation, as long as no serious adverse effects occur. Evidence is insufficient to recommend one opioid over another; however, short-acting opioids are probably safer for initial therapy because there is less risk of inadvertent overdose. Transitioning to around-the-clock dosing of long-acting opioids may lead to more consistent pain control, improved adherence, and lower risk of abuse. Methadone If methadone is used, it should be initiated and titrated cautiously by a physician familiar with its use and risks (Grade: strong recommendation, moderate-quality evidence). The use of methadone for chronic noncancer pain has increased; however, few trials have evaluated its risks and benefits. In addition, several epidemiologic studies suggest an increase in methadone-related deaths in the United States. Prescribing physicians should be familiar with its complicated and variable pharmacodynamics, and potential risks. Methadone dosing relative to other opioids is variable, and conversion to methadone should be performed cautiously. Monitoring Patients should be reassessed periodically and when warranted by changing circumstances (Grade: strong recommendation, low-quality evidence). Urine drug testing or other methods to determine adherence should be performed in patients at high risk of aberrant drug-related behaviors (Grade: strong recommendation, low-quality evidence), and considered in patients at low risk (Grade: weak recommendation, lowquality evidence). Regular monitoring of all patients undergoing chronic opioid therapy is important in determining whether the treatment is benefiting the patient, assessing whether restructuring the treatment plan or adding additional services would be helpful, and reevaluating the benefits versus risks. Risk stratification is useful in guiding the intensity and frequency of monitoring. Regular, repeated assessments that address a variety of factors are likely to be most effective. Because selfreport may be unreliable for determining adherence, other methods (e.g., urine drug screening, pill counts, caregiver interviews) may be considered. High-risk patients Chronic opioid therapy may be used in patients with a history of drug abuse, psychiatric issues, or serious aberrant drug-related behaviors only if more stringent monitoring is implemented. However, consultation with a mental health

or addiction subspecialist should be strongly considered. If a patient undergoing chronic opioid therapy engages in aberrant drug-related behavior, use of the therapy should be reevaluated (Grade: strong recommendation, low-quality evidence). Chronic noncancer pain is common in patients with a history of drug abuse, psychiatric issues, or serious aberrant drug-related behaviors. Although the use of chronic opioid therapy is challenging in these patients, it may be beneficial to some. Potential risks may be minimized with more frequent and intense monitoring, limited prescription quantities, prescription monitoring programs, and physician consultation with a mental health or addiction subspecialist. If aberrant behavior occurs, reevaluation of the use of chronic opioid therapy is required. However, the physicianâ&#x20AC;&#x2122;s response should consider the seriousness of the behavior, the cause of the behavior, the likelihood that the behavior will recur, and the clinical context. Higher dosages and discontinuation of therapy When repeated dosage escalations occur, physicians should evaluate potential causes and reassess benefits versus harms (Grade: strong recommendation, low-quality evidence). In patients who require relatively high dosages of therapy, physicians should regularly evaluate for unique opioidrelated adverse effects, changes in health status, and adherence; more frequent follow-up should be considered (Grade: strong recommendation, low-quality evidence.) Opioid rotation should be considered if intolerable adverse effects occur or if treatment benefit is inadequate (Grade: weak recommendation, low-quality evidence). Chronic opioid therapy should be tapered or weaned in patients who engage in aberrant drug-related behavior, have no progress toward therapeutic goals, or experience intolerable adverse effects (Grade: strong recommendation, low-quality evidence). Progressively higher opioid dosages may improve pain control in some patients, but repeated escalations may have limited usefulness and may be a marker for substance use disorder or diversion. There is little evidence to guide opioid prescribing at higher dosages. However, when dosages reach 200 mg of morphine daily, or the equivalent, increased monitoring may be appropriate. Rotating different opioids is an option for some patients who have intolerable adverse effects or inadequate benefit of treatment despite dosage increases. Tapering or weaning of therapy often can be achieved in an outpatient setting. A slower dosage reduction may reduce withdrawal effects, and referral to a detoxification program may be beneficial.

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American Family Physician Adverse effects Physicians should anticipate, identify, and treat common opioid-related adverse effects (Grade: strong recommendation, moderate-quality evidence). Anticipation and treatment of adverse effects help maintain a favorable balance of benefits to harms, decrease the risk of discontinuation, and may allow for the use of higher opioid dosages if needed. Constipation and nausea/vomiting are common adverse effects associated with opioid use. Sedation, pruritus, and myoclonus are also possible. Psychotherapeutic cointerventions Adjunctive nonopioid therapy, such as psychotherapeutic interventions, functional restoration, and interdisciplinary therapy, should be routinely added to chronic opioid therapy in patients with chronic noncancer pain (Grade: strong recommendation, moderate-quality evidence). When chronic noncancer pain is accompanied by comorbidities, impaired function, or psychological disturbances, chronic opioid therapy is most effective when part of a multimodality treatment strategy. Cognitive behavior therapy has consistently been shown to be effective in patients with chronic noncancer pain. Other adjunctive treatment strategies include progressive relaxation, biofeedback, functional restoration, and inter- or multidisciplinary pain management approaches. Opioid-related cognitive impairment Physicians should counsel patients about transient or lasting cognitive impairment from chronic opioid therapy that may affect driving and work safety (Grade: strong recommendation, low-quality evidence). Opioid use may cause somnolence, clouded mentation, decreased concentration, and slower reflexes. Patients should be counseled not to drive or engage in potentially dangerous activities when impaired, and

that the risk of impairment is higher with treatment initiation, with dosage increases, and when combining opioids with other drugs or substances that effect the central nervous system (e.g., alcohol). Medical home and consultation Patients should identify a physician to coordinate consultation and communication among all health care professionals involved in the patient’s care (Grade: strong recommendation, low-quality evidence). Consultation, including interdisciplinary pain management, should be pursued if the patient may benefit from additional skills or resources (Grade: strong recommendation, moderate-quality evidence). Studies have shown that patients have better outcomes when they have a physician who accepts primary responsibility for most of their care and coordinates the care from other physicians when needed. This medical home model does not require the primary physician to prescribe and monitor the patient’s chronic opioid therapy, although the physician’s coordination of other resources (e.g., pain centers) is crucial. Breakthrough pain If patients undergoing around-the-clock chronic opioid therapy have breakthrough pain, physicians may consider as-needed administration based on the initial and ongoing assessment of benefits versus risks (Grade: weak recommendation, lowquality evidence). Breakthrough pain may not be related to the underlying condition; therefore, its assessment, including diagnostic testing, follow-up, and possible referral, should be separate from that of baseline pain. Additional as-needed opioid therapy is an option for breakthrough pain; however, the therapeutic benefits should be weighed carefully against the potential harms, and nonpharmacologic and nonopioid therapies should be considered.

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Source: Adapted from Am Fam Physician. 2009;80(11):1315-1318.

Cardiology

Higher Prevalence Rate of CHD in ‘Apple Type of Obesity’ Cases as Compared to ‘Pear Type Obesity’ Cases OP PATIDAR

Abstract Background: In general obesity can be categorized as upper truncal obesity and lower truncal obesity also known as ‘apple type of obesity’ and ‘pear type of obesity’, respectively. Although, there is high prevalence rate of coronary heart disease (CHD) in all obese persons whose body mass index (BMI) are >25, as compared to normal population. But, centrally obese persons are highly prone to develop CHD as compare to other type of obesity which is evaluated in this study. Material and methods: Hundred cases of CHD (64 males, 36 females) aged from 22 to 65 years attending SRG Hospital, Jhalawar were screened for conventional coronary risk factors like diabetes mellitus (DM), hypertension, hypercholesterolemia, tobacco chewing, smoking and obesity. BMI and waist-hip ratio (WHR) were taken as a criteria for categorization of obesity. Results: In this study, total 100 cases, (64 male, 36 female) were studied, out of them 38 cases were average built, 40 cases were overweight and obese, 22 cases were underweight. Out of these 40 overweight and obese cases, 25 cases were of apple type of, 10 cases were of pear type obesity and five cases of mixed type obesity cases. These 25 cases of apple type obesity were more prone to CHD and other comorbid conditions like type 2 DM (T2DM) and hypertension. Conclusions: In this study, the incidence of CHD was higher in central obesity cases irrespective of their BMI. Both high waist circumference (WC) and high WHR was an best index of abdominal obesity to predict the incidence of CHD in overweight and obese group.

Keywords: Obesity, apple type obesity (android), pear type obesity (gynoid), BMI, coronary heart disease, waisthip ratio

Introduction

Obesity Obesity is a state in which there is generalized accumulation of excess fat in the body leading to a body weight of >20% of the required weight. Obesity invites disability, disease and premature death. It is one of the most common disorders in medical practice. In the urban population of India, refined wheat and rice have virtually displaced coarse grains and millets as the staple cereal, resulting in a substantial reduction in fiber content in the diet and possibly, also the content of micronutrients such as vitamin B complex, zinc and chromium, etc. As the population ascends the socioeconomic scale, cereal intake declines and the intake of sugar and fats generally increase. Convenience and fast foods find increasing acceptance, especially in the context of globalization. While a third of India’s population still falls below the poverty line, there has been a steady growth of the relatively affluent urban

*Assistant Professor, Dept. of General Medicine, Jhalawar Medical College Jhalawar, Rajasthan

middle class, now estimated to number over 200 million. Those who have achieved affluence within a lifetime constitute a good proportion of this middle class. On the basis of distribution of excess body fat obesity is broadly divided into following three categories.

Android (Apple Type) Android type of obesity is likened to the shape of an apple. The shoulders, face, arms, neck, chest and upper portion of the abdomen are bloated. The stomach gives a stiff appearance. So, also the arms, shoulders and breast. The back seems to be erect but the neck is compressed and there will be protruding chest because of the bulk in the stomach. The lower portion of the body, the hips, thighs and legs are thinner beyond proportion in comparison with the upper part. In these persons, the vital organs affected will be mostly the heart, liver, kidneys and lungs. Though this type of obesity is found more in males it is common in females too. Those females, who are under hormone treatment for their menstrual abnormalities or after childbirth, are more prone to this type of obesity. It occurs in females around menopause too due to thyroid gland’s functional disturbance. Android type of obesity is a

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Cardiology major risk for heart damage and heart disease due to high cholesterol.

Gynoid (Pear Type) In this type the lower part of the body has the extra flesh. This type of obesity is also common to both sexes though females are more affected. Gynoid type of obesity is similar to pears. The flesh is somewhat flabby in the abdomen, thighs, buttocks and legs. The face and neck mostly give a normal appearance. In some persons, the cheeks may be drawn too. As these persons grow old the whole figure assumes a stooping posture and the spine is never erect due to the heavy hips and thighs. The vital organs affected mostly are the kidneys, uterus, intestines, bladder and bowls. In this type of obesity, exercises or dieting will not help appreciably in reducing weight.

peripheral pulsation, heart, lung and carotid exami足 nations were done. Their height (in m) and weight (in kg) were recorded to calculate their BMI. BMI was calculated by standard formula: BMI =

Weight (kg)

(Height (m2) Their routine examinations like complete blood count (CBC), sugar, urea, creatinine, lipid profile, ECG, chest X-ray and cardiac enzyme estimations were done in required cases. Waist and hip measurements were taken just above the belly button and at the hips on the widest part of buttocks, respectively. RESULTS

Obesity and overweight are best defined using the body mass index (BMI). This index is determined by dividing body weight in kilograms by the square of the height in meters: BMI = W/H2. The normal rate for BMI is 18.5-25. A BMI between 25 and 30 kg/m2 is defined as overweight and a BMI above 30 kg/m2 is defined as obesity. Visceral fat can be used as an index of central adiposity. An increase in visceral fat reflects central obesity and increases health risks. The waist circumference (WC) is used to assess the amount of visceral obesity. A WC in men 94 cm or more, and in women 80 cm or more, is the threshold for high health risk but desirable abdominal girth level should be <80 cm.

Results have shown that out of 100 cases, 38 cases were average built (25 male, 30 female), 40 cases were overweight and obese (25 male, 15 female), 22 cases were underweight (14 male, 8 female). Out of 100, 58 cases were from rural area and 42 cases were from urban area. In overweight and obese group out of 40 cases, 25 cases were of apple (android) type of obesity, 10 cases were of pear (gynoid) type of obesity, five cases were of mixed type of obesity observed. Apple type of obesity were common in males (out of 25, 18 males, 7 females) while pear type of obesity were more common in females (out of 10, 8 females, 2 males). Out of 100 cases, 58 cases were having hypertension, 22 cases were having type 2 DM (T2DM) and five cases were of hypothyroidism. Total 52% cases were consuming tobacco in different ways like smoking, tobacco chewing, or using tobacco containing toothpaste. Out of 100, 38 cases of average built had their BMI from 19 to 24, 40 overweight cases had their BMI from 25 to 35, and in 22 underweight group cases the BMI <18.5. All healthy average built cases were having their waist-hip ratio (WHR) <0.8 in female and <0.9 in male while in overweight and obese group this ratio was >0.8 in female and >0.9 in male. In obese group, apple type of obesity cases were having more comorbid conditions like hypertension, T2DM and more cardiac damage. The higher incidence of CHD were observed in those cases who were having their WC >94 cm and 80 cm in male and female, respectively.

MATERIAL and METHODS

DISCUSSION

One hundred (64 males, 36 females) cases aged from 22 to 65 years of coronary heart disease (CHD) attending SRG Hospital were studied. Their detail clinical history and examinations were carried out. Other than their physical examinations like pulse, blood pressure (BP),

We know that the incidence of CHD and other comorbid conditions like hypertension, T2DM, cerebrovascular accident (CVA), gallstone diseases and certain type of cancers are more prevalent in obese group of patient. Further, studies support that excess

The Third Type Besides android and gynoid, there is one more type of obesity. Some people do not belong to any of the above type of obesity. Their whole body from head to toe looks like a barrel. Their gait is more like rolling rather than walking. The fat tissues in their body hinder the movement of all the internal organs and consequently affect their brisk functioning. For them any exercise is difficult due to the enormous size of the body. So such persons should follow a strict diet and do plenty of exercise.

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Cardiology accumulation of fat specially in upper part of body and in intra-abdominal region, also known as apple type of obesity, is more commonly associated with CHD as compared to those who have accumulation of fat on hip and thigh areas which is known as ‘pear type of obesity’. This is possibly because adipocytes of intra-abdomen are more active than other adipocytes and they liberate more harmful free fatty acids directly into portal circulation where they get metabolized in liver and produce harmful metabolites, free fatty acid and more free radicals which may be directly or indirectly responsible for premature atherosclerosis and other endothelial dysfunctions along with other metabolic disorders like T2DM and CVA and certain cancers. In this study, it was observed that incidence of obesity was also increasing in society. It was observed that 40% cases were obese in this study, while few decade back the incidence of obesity was about 10% in general population. For more than two decades, a plethora of studies have clearly shown that the distribution of body fat, especially excess abdominal fat accumulation (which can be readily estimated by the measurement of waist girth), is predictive of both prevalent and incident coronary artery disease (CAD) and diabetes - this relationship being largely independent from the contribution of total body fat.1 In this study, the incidence of CHD was higher in central obesity cases irrespective of their BMI, which is supported by a recent meta-analysis of all studies on the subject, which confirmed that abdominal obesity was associated with 70% higher mortality in people with and without high BMI.2 Both high WC and high WHR were used as an index of abdominal obesity.2 But, in this study, no observations were recorded for mortality incidence. Thus abdominal obesity is associated with higher incidence of CHD even in apparently healthy people without high BMI. Similar things were observed in this study. In patients with asymptomatic CHD, excess visceral adipose tissue/liver fat deposition is clearly associated with diabetogenic and atherogenic metabolic abnor‑ malities.1,3,4 In clinical practice, these people can be readily identified by finding the hypertriglyceridemic waist (WC >90 cm and triglycerides >175 mg/dl or 2 mmol/l).5,6 People with central obesity have higher mortality even when the BMI is normal and therefore WC should be recorded and pursued in every individual in addition

to BMI for better risk stratification and therapeutic considerations.2 Recent studies have confirmed that an elevated BMI was indeed associated with a 36% lower mortality in CHD patients. However, abdominal obesity was associated with 70% higher mortality in people with and without high BMI. Both high waist WC and high WHR were used as an index of abdominal obesity.2 So, it is suggested that WC and WHR are more reliable than BMI in stratifying mortality risk in CHD patients, and WC and/or WHR should be documented in individuals with CHD and normal BMI for better risk stratification and therapeutic considerations.2 BMI (weight in kilograms divided by the square of the height in meters) is promulgated by the World Health Organization as the most useful epidemiological measure of obesity. It is nevertheless a crude index that does not take into account the distribution of body fat, resulting in variability in different individuals and populations. Waist-hip circumference ratio (WHR), waist-height ratio (WHR) and WC are commonly used to predict the risk of obesity related morbidity and mortality as they account for regional abdominal adiposity. BMI >25.0 and >30.0 kg/m2 was taken as cut offs for overweight and obesity, respectively. WC cut-offs were taken as >94 cm for males and >80 cm for females to define overweight.7 The cut-off used for WHR were >0.9 for males and >0.8 for females.8 Many other studies have shown that WC >102 cm in male and >88 cm in female were having higher incidences of diseases than people with smaller waist size. The ICMR task force project9 reported 65% prevalence of high WHR in urban Delhi and 52% in rural Haryana in 1994, using the criteria (WHR: M: >0.9, F: >0.8). Serial epidemiological surveys in urban Rajasthan had shown the prevalence at 60% during 1994,10 63% during 200111 and 79% during 200312 using the criteria (WHR: M: >0.9, F: >0.8). On the contrary obese patients have a better survival when they develop a heart attack or undergo coronary procedures such as angioplasty, stent or bypass surgery. This phenomenon has been commonly referred to as the ‘obesity paradox’.13,14 Conclusions So, we should spread the awareness in society that accumulation of fat in abdominal cavity or enlarged abdominal belly is more dangerous and they must be encouraged to reduce the weight either by some special

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Cardiology exercises oriented to reduce the girth of abdominal belly or by dietary restrictions. For healthy living we can follow arbitrary formula of 80 to avoid heart attack before 80. Keep lower BP, bad cholesterol, resting heart rate, fasting sugar and abdominal girth levels <80. Take 80 mg of aspirin, or 80 mg atorvastatin if prescribed for prevention. References 1. Després JP. Excess visceral adipose tissue/ectopic fat the missing link in the obesity paradox? J Am Coll Cardiol 2011;57(19):1887-9. 2. Coutinho T, Goel K, Corrêa de Sá D, Kragelund C, Kanaya AM, Zeller M, et al. Central obesity and survival in subjects with coronary artery disease: a systematic review of the literature and collaborative analysis with individual subject data. J Am Coll Cardiol 2011;57(19):1877-86. 3. Després JP, Lemieux I, Bergeron J, Pibarot P, Mathieu P, Larose E, et al. Abdominal obesity and the metabolic syndrome: contribution to global cardiometabolic risk. Arterioscler Thromb Vasc Biol 2008;28(6):1039-49. 4. Després JP, Moorjani S, Lupien PJ, Tremblay A, Nadeau A, Bouchard C. Regional distribution of body fat, plasma lipoproteins, and cardiovascular disease. Arteriosclerosis 1990;10(4):497-511. 5. Lemieux I, Pascot A, Couillard C, Lamarche B, Tchernof A, Alméras N, et al. Hypertriglyceridemic waist: A marker of the atherogenic metabolic triad (hyperinsulinemia; hyperapolipoprotein B; small, dense LDL) in men? Circulation 2000;102(2):179-84.

6. Lemieux I, Poirier P, Bergeron J, Alméras N, Lamarche B, Cantin B, et al. Hypertriglyceridemic waist: a useful screening phenotype in preventive cardiology? Can J Cardiol 2007;23 Suppl B:23B-31B. 7. World Health Organization. The Asia-Pacific Perspective: Redefining Obesity and its Treatment. World Health Organization: Geneva, Switzerland, 2000. 8. Webb GP. Nutrition: A Health Promotion Approach. 2nd edition, Arnold Publishers: London 2002:p.186. 9. ICMR Task Force Project on Collaborative Study of Coronary Heart Study. 10. Gupta R, Prakash H, Majumdar S, Sharma S, Gupta VP. Prevalence of coronary heart disease and coronary risk factors in an urban population of Rajasthan. Indian Heart J 1995;47(4):331-8. 11. Gupta R, Gupta VP, Sarna M, Bhatnagar S, Thanvi J, Sharma V, et al. Prevalence of coronary heart disease and risk factors in an urban Indian population: Jaipur Heart Watch-2. Indian Heart J 2002;54(1):59-66. 12. Gupta R, Sarna M, Thanvi J, Rastogi P, Kaul V, Gupta VP. High prevalence of multiple coronary risk factors in Punjabi Bhatia community: Jaipur Heart Watch-3. Indian Heart J 2004;56(6):646-52. 13. Romero-Corral A, Montori VM, Somers VK, Korinek J, Thomas RJ, Allison TG, et al. Association of bodyweight with total mortality and with cardiovascular events in coronary artery disease: a systematic review of cohort studies. Lancet 2006;368(9536):666-78. 14. Lavie CJ, Milani RV, Ventura HO. Obesity and cardiovascular disease: risk factor, paradox, and impact of weight loss. J Am Coll Cardiol 2009;53(21):1925-32.

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Low Cholesterol Linked to Anxiety, Depression, Suicide, Hemorrhagic Stroke and Cancers People with very low cholesterol levels are at increased risk of developing stomach cancer, according to a study published in the International Journal of Cancer. The study involved 2,600 residents of Hisayama, Japan, who were followed for 14 years. Gastric cancers developed in 97 subjects. After accounting for age and gender, stomach cancer rates rose significantly with descending cholesterol level. For example, among subjects with the highest cholesterol levels, the gastric cancer rate was the equivalent of 2.1 cases per 1,000 persons per year; among those with the lowest cholesterol, the rate was 3.9 per 1,000 persons per year. Patients with low serum cholesterol should consider periodic gastrointestinal examination for the prevention of stomach cancer. Low cholesterol has been earlier linked to depression, anxiety and suicide in both men and women. Another earlier report has also shown that people with cholesterol level below 180 had twice the risk of brain hemorrhage as compared to those with cholesterol levels of 230.

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Cardiology

Irreversible Thyrotoxic Dilated Cardiomyopathy: Case Reports and Review of Literature Ibraheem Khan*, GN Saxena**, Prakash Keshwani†, Swati Srivastava‡, Sher Singh#, Gunjan Sharma#

Abstract Irreversible dilated cardiomyopathy due to thyrotoxicosis is a rare clinical entity. We report two cases, one who presented with congestive cardiac failure and other presented with severe left ventricular dysfunction and atrial fibrillation. Both cases were diagnosed as dilated cardiomyopathy with severe left ventricular dysfunction (ejection fraction <30%) due to thyrotoxicosis. Inspite of vigorous medical therapy, there was only symptomatic improvement. Restoration of euthyroid levels did not revert the cardiomyopathy but led to definite clinical improvement.

Keywords: Irreversible dilated cardiomyopathy, thyrotoxicosis, left ventricular dysfunction

ardiomyopathies are diseases that involve the myocardium directly and are not secondary to hypertension, congenital, valvular, coronary artery disease or pericardial disease.1 It has generally been accepted that thyrotoxicosis may be associated with high output heart failure in patient with heart disease, symptomatic or not.2 Here, we report two cases of dilated cardiomyopathies who presented with initial symptoms of breathlessness and palpitations that did not resolve inspite of restoration of thyroid levels. Case presentation 1 A 35-year-old female patient presented with shortness of breath and bilateral pedal edema since 15 days. There was no history of sore throat, paroxysmal nocturnal dyspnea, chest pain, oliguria and hematuria. There was no history of any cardiac disease in the past. She was nonsmoker and nonalcoholic. She did not receive or take any medicine.

*Assistant Professor **Ex-Professor Dept. of Medicine †Professor Dept. of Endocrinology ‡Associate Professor #Residents Dept. of Medicine, SMS Medical College, Jaipur, Rajasthan Address for correspondence Dr Ibraheem Khan Samraya, Weir, Bharatpur, Rajasthan - 321 408 E-mail: imedicine2008@gmail.com

On physical examination, she was afebrile, pulse was 112/min irregularly irregular, blood pressure was 110/70 mmHg and respiratory rate was 22/min. She had pallor, engorged neck veins with raised internal jugular venous pressure and bilateral pitting pedal edema. Fine tremors were present in both hands. There was bilateral thyroid swelling with tender hepatomegaly. The apex impulse was in 5th intercostal space, hyperdynamic in nature just outside the midclavicular line. First heart sound was soft, S2 audible and S3 gallop was present. There were Grade 3 pansystolic flow murmur in mitral area. There were no rales in chest. The chest X-ray showed cardiomegaly (Fig. 1). The ECG showed left ventricular with left bundle branch block. Two-dimensional echocardiography was suggestive of

Figure 1. The X-ray of chest showing cardiomegaly.

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Cardiology Case presentation 2 A 65-year-old male patient presented with chief to complaints of progressive dyspnea on exertion and palpitation since two months. There was no history of orthopnea, paroxysmal nocturnal dyspnea, chest pain, oliguria and hematuria. There was no history of any cardiac disease in the past. He was taking antithyroid drug since one year.

Figure 2. Two-dimensional echocardiography suggestive of dilated cardiomyopathy with left ventricular ejection fraction of 20% with severe mitral regurgitation, severe tricuspid regurgitation with global hypokinesia.

On physical examination, he was afebrile, pulse was 122/min irregularly irregular, blood pressure was 110/70 mmHg and respiratory rate was 22/min. There was no thyroid swelling. Fine tremors were present in both hands. The apex impulse was in 5th intercostal space, hyperdynamic in nature just outside the midclavicular line. First heart sound was loud, S3 gallop was present. There were Grade 3 pansystolic flow murmur in mitral area. There were no rales in chest. The chest X-ray showed cardiomegaly. The ECG showed atrial fibrillation. Two-dimensional echocardiography was suggestive of dilated cardiomyopathy with left ventricular ejection fraction of 25% with severe mitral regurgitation, moderate tricuspid regurgitation and pulmonary hypertension with global hypokinesia (Fig. 3). The thyroid hormone profile was done: serum T3 1.22 (0.6-1.81 ng/ml), serum T4 11.01 mg/dl (4.5-10.9 mg/dl) and serum TSH 0.12 (3.5-5.50 mIU/ml). Discussion

Figure 3. Two-dimensional echocardiography suggestive of dilated cardiomyopathy with left ventricular ejection fraction of 25% with severe mitral regurgitation, moderate tricuspid regurgitation and pulmonary hypertension with global hypokinesia.

dilated cardiomyopathy with left ventricular ejection fraction of 20% with severe mitral regurgitation, severe tricuspid regurgitation with global hypokinesia (Fig. 2). On investigations, hemoglobin (Hb) was 8.6 g/dl total leukocyte count (TLC) 7,250/mm3 with normal renal and liver profile. Troponin T was negative. Antistreptolysin O titer was <200 U. Blood culture was also negative. The thyroid hormone profile: Serum free tri-iodothyronine (FT3) was 7.75 ng/dl (1.8-4.2 pg/ml), serum free thyroxine (FT4) was 4.48 mg/dl (0.89-1.76 ng/dl) and serum thyroid-stimulating hormone (TSH) was 0.035 (0.4-4 mIU/ml).

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The cardiovascular manifestations of thyrotoxicosis may be due to direct effects of thyroid hormones at the cellular level, their interactions with the sympathetic nervous system, or alterations of peripheral circulation and metabolism.1 Sinus tachycardia in thyrotoxicosis can occur at rest, during sleep and during exercise. It is hypothesized that thyroid hormones have direct effects on the conduction system, possibly via cellular changes in cation transport including a decrease of atrial excitation threshold, an increase of sinoatrial node firing and a shortening of conduction tissue refractory time.3 Atrial fibrillation occurs in 5-15% of hyperthyroid patients.4 It has been reported that approximately 6% of patients with hyperthyroidism present with congestive heart failure, half of whom have left ventricular systolic dysfunction.5 Few cases of reversible dilated cardiomyopathy recovered through the use of antithyroid medications.6 Chronic persistent tachyarrhythmias and cardiac

Cardiology sensitivity to b-adrenergic stimulation are likely to contribute to the development of left ventricular systolic dysfunction in patients with thyrotoxicosis.7 Conclusion These cases further add to the evidence of association between thyrotoxicosis and dilated cardiomyopathy in adults. It is important to recognize that dilated cardiomyopathy may be an initial manifestation of thyrotoxicosis as it can be reversed with use of antithyroid drugs.6 References 1. Ellen WS, Gordon HOW. The heart in endocrine disorders. In: Heart Disease a Textbook of Cardiovascular Medicine. 6th edition, Eugene Braunwald, Douglas P Zipes, Peter Libby (Eds.), 2001:p.1751-806.

2. Panagoulis C, Halapas A, Chariatis E, Driva P, Matsakas E. Hyperthyroidism and the heart. Hellenic J Cardiol 2008;49(3):169-75. 3. Woeber KA. Thyrotoxicosis and the heart. N Engl J Med 1992;327(2):94-8. 4. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med 2001;344(7):501-9. 5. Siu CW, Yeung CY, Lau CP, Kung AW, Tse HF. Incidence, clinical characteristics and outcome of congestive heart failure as the initial presentation in patients with primary hyperthyroidism. Heart 2007;93(4):483-7. 6. Boccalandro C, Boccalandro F, Orlander P, Wei CF. Severe reversible dilated cardiomyopathy and hyperthyroidism: case report and review of the literature. Endocr Pract 2003;9(2):140-6. 7. Alidjan F, Ezzhati M, Bruggeling W, van Guldener C. Takotsubo cardiomyopathy precipitated by thyrotoxicosis. Thyroid 2010;20(12):1427-8.

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Revival of Heart after Death ÂÂ

It is possible to save the life of a person within 10 minutes of death.

ÂÂ

Consciousness does not leave the body till the brain is alive.

ÂÂ

It takes upto 10 minutes for the brain to die permanently and once that happens, life cannot be brought back.

ÂÂ

The Savitri-Satyavan story can be equated to be the first mythological example of revival with Savitri fighting with Yamraja and reviving Satyavan’s life back after sudden cardiac death.

ÂÂ

Following are the terms which, if learnt properly, can save the life of a person: zz

Savitri Yagna is the process of learning to revive a person after death and the technique is called CPR 10.

Savitri Dharma means that one’s purpose of life should be to save somebody who has died accidentally and suddenly before time.

Savitri Mantra is the mantra which should be recited by everybody till it is remembered at the level of your consciousness and the mind, “Marne ke dus minute ke under kam se kam dus minute tak 10 x 10 = 100 per minute ki speed se apni chhati peetne ke badle mare hue aadmi ki chhati peeto”.

Next step is Savitri Aasan i.e. in which position to save the life of the person. For this the dead person is made to lie on the floor and bystander should sit on his knees by his side.

Next is Savitri Mudra, which means getting ready to compress the center of the chest of the dead victim with both arms outstretched keeping the elbows straight.

Savitri House is the location where the compression has to be done on the dead person; this should be in between the two nipples.

Savitri Karma means to compress the center of the chest of the dead victim with a speed of 10 x 10 = 100 per minutes.

With all this, it is possible to revive 80% of the people who die suddenly before time especially due to heart attack, drowning and electrocution.

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critical care

Anaphylactic Shock: A Rare Presentation of Phenytoin Drug Reaction Amit D Bhatt*, Anjali N Joshi**, AP Jain†

Abstract The adverse effects of phenytoin are well-documented in literature. We describe a case of severe anaphylactic shock following intravenous administration of phenytoin, a rarely described and known entity.

Keywords: severe anaphylactic shock, phenytoin toxicity

henytoin is a very commonly used drug in medical practice. However, it is not adverse to side effects due to hypersensitivity some of which are well-documented in literature as StevensJohnson syndrome, cerebellar toxicity and Drug Reaction with Eosinophilia and Systemic Symptom (DRESS) syndrome.1-3

We describe a case of severe anaphylactic shock following intravenous (IV) administration of phenytoin, a rarely described and known entity. Our patient, 40-year-old male presented with generalized tonic clonic seizures (6 episodes in 1 day). He was managed with IV lorazepam followed by intravenous loading dose of phenytoin 600 mg (15 mg/kg in 100 ml of 0.9% sodium chloride injection) over 30 minutes (20 mg/min). The patient developed erythematous rash all over his body within 15 minutes of the infusion followed by respiratory distress and wheeze. This was followed by profound hypotension (BP 60 systolic mmHg). A diagnosis of anaphylactic shock was made based on clinical picture and was managed as per standard protocol with IV infusion of fluids, adrenaline and steroids. The patient’s blood sugar levels, serum electrolytes and ECG were found to be normal. Patient recovered well from the episode in three days without after effects. Literature search for probable cause of such manifestation *Lecturer **Resident Postgraduate †Director Professor and Head Dept. of Medicine, Mahatma Gandhi Medical Sciences, Sewagram, Wardha, Maharashtra Address for correspondence Dr Amit D Bhatt Dept. of Medicine, Mahatma Gandhi Medical Sciences, Sewagram Wardha - 442 102, Maharashtra E-mail: amitbhtt.md@gmail.com

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revealed an interesting point. Such shock may be due to rapid loading rates of phenytoin in excess of 50 mg/min, the anaphylaxis being due to propylene glycol. It is known fact that IV phenytoin precipitates if diluted with IV fluids such as 5% dextrose and can only be diluted with 0.9% sodium chloride. To augment its solubility, IV phenytoin is formulated with 40% propylene glycol, a diluent. Propylene glycol has been attributed in literature to be cardiotoxic leading to hypotension and arrhythmias.4,5 This may be proposed as a likely explanation to the episode. It, however fails to explain the dermatological and respiratory manifestations. Wisdom to be learnt from the episode is to know the spectrum of phenytoin toxicity and especially to control the infusion rates so as to prevent shock and cardiotoxicity. References 1. Rzany B, Correia O, Kelly JP, Naldi L, Auquier A, Stern R. Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis during first weeks of antiepileptic therapy: a case-control study. Study Group of the International Case Control Study on Severe Cutaneous Adverse Reactions. Lancet 1999;353(9171):2190-4. 2. O’Brien TJ, Meara FM, Matthews H, Vajda FJ. Prospective study of local cutaneous reactions in patients receiving IV phenytoin. Neurology 2001;57(8):1508-10. 3. Allam JP, Paus T, Reichel C, Bieber T, Novak N. DRESS syndrome associated with carbamazepine and phenytoin. Eur J Dermatol 2004;14(5):339-42. 4. Wheless JW. Pediatric use of intravenous and intramuscular phenytoin: lessons learned. J Child Neurol 1998;13 Suppl 1:S11-4; discussion S30-2. 5. Ramsay RE, DeToledo J. Intravenous administration of fosphenytoin: options for the management of seizures. Neurology 1996;46(6 Suppl 1):S17-9.

Critical Care

Anaphylaxis to IV Atropine: A Case Report DA Hiremath

Abstract A 35-year-old woman, who was administered intravenous (IV) atropine as a part of anesthetic management of fibroadenoma of breast, developed anaphylactic shock and required adrenaline to maintain perfusion pressure. Patient improved.

Keywords: Anaphylaxis, atropine

dverse drug reactions during anesthesia appear to be on increase and include those of allergic origin.1 The true incidence is unknown; Fisher et al2 report an incidence of one in 5,000 to one in 20,000 cases, with an associated mortality of 3-4%. The increase in incidence of allergic reactions in the last few years is undisputed.3 This is attributed to the greater number of drugs used perioperatively, multiplicity of exposure to the same or related drugs and a history of atopy.4

For an anaphylactic reaction to occur, previous exposure to the drug (or similar agent) is necessary. This results in the production of specific antibodies. Re-exposure then induces release of chemical mediators from basophils and mast cells and produces reactions.5 The nonimmune anaphylactoid reactions result from the interaction between the agents and cells, which trigger a release of histamine; previous exposure in not necessary. Occasionally, both types of reactions are implicated6 and it is only possible to separate them by specific laboratory tests.7 We report a case of anaphylaxis after intravenous (IV) administration of atropine. Case History A 35-year-old woman was scheduled for elective excision of fibroadenoma of right breast. It was ASA (American Society of Anesthesiologists) Grade I case with no history of allergy to any drugs and food items in the past. There was no history of previous blood transfusion or any surgery where anesthesia was administered.

Professor Dept. of Anesthesiology SN Medical College, Bagalkot - 587 102, Karnataka E-mail:dahiremath@yahoo.com

Her blood pressure was 120/80 and heart rate was 72 beats/minutes in the anesthesia room. Ringer lactate was started and she was given IV atropine 0.01 mg/kg as a part of our anesthetic management using atropine, ketamine and midazolam. She became anxious and drowsy shortly afterwards, she developed generalized urticaria over the face, neck, including upper chest and upper limbs also. Her systolic blood pressure dropped from 120 to 60 mmHg. The heart rate increased to 120 beats/minute. ST-T segment depression (â&#x20AC;&#x201C;2 mV) was seen. No error was detected in the monitoring and infusion systems. There were no changes in the cardiac rhythm, end tidal carbon dioxide (CO2) and oximetry. The patient developed bronchospasm and stopped breathing. She was intubated and ventilated with 100% O2. Peripheral pulses were impalpable; pupils were dilated but reactive to light. She was placed in the head down position and IV infusion rate of ringer lactate was increased. IV hydrocortisone 200 mg and adrenaline 0.5 mg subcutaneously was given. The blood pressure increased to 100/70 mmHg 15 minutes later and heart rate came down to 100 beats/minute. Antihistamines were also given IV, steriods and antihistamines were continued to 48 hours. The clinical picture dissolved completely in approximately 30 minutes. The surgery was postponed and the patient was monitored and discharged after two days. Discussion There are many reports of adverse reactions after IV atropine8-13 and development of erythematous rashes over chest, face and neck is a very common allergic manifestation. Clinically allergic reactions involve many organs. The severity of symptoms, the onset and duration are extremely variable (Table 1). An allergic reaction occurs and tends to be severe after IV administration as in our patient. Histamine is the

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Critical Care Table 1. Grades of Severity of Allergic Reactions12 Grade Clinical features I

Cutaneous features, erythema, urticaria, flushing, abdominal pain

Tachycardia, hypotension, bronchospasm

III

Cardiovascular collapse

Cardiac arrest

Table 2. Diagnostic Tests after Allergic Reaction12 Primary diagnosis

Secondary diagnosis

Routine laboratory tests, plasma IgE levels, complement levels, basophil count

In vivo tests intradermal tests, passive transfer (or Prausnit Kustner) In vitro tests: Leukocyte migration inhibition test, lymphoblast transformation test Radio-allergosorbent test, leukocyte histamine liberation test, IgE inhibition test

essential chemical mediator after anaphylaxis although atleast 20 other chemicals are involved.9 The clinical symptoms are cutaneous rashes11 as a result of histamine-provoked capillary dilatation and increased permeability and usually occur over face, neck and upper chest. These rashes disappear in few hours to 1-2 days.5 The hypotension is caused by vasodilatation and reduced venous return as a result of increased capillary permeability. The tachycardia is due to release of endogenous catecholamines. The reported incidence of cardiovascular collapse after anaphylaxis varies.11 Le cam et al13 reported an incidence of only one in 5,000. This is in contrast to the Fisher and Baldo9 who reported that cardiovascular collapse was the commonest life-threatening features in 82% of patients. The bronchospasm in this case is due to the histamine release.12 A severe allergic reaction requires prompt and aggressive treatment.3,6,7 In this case, steroids and antihistamines were given to counteract anaphylaxis and some have used isoprenaline and diphenhydramine.5,7 It is very important to detect the drug responsible after allergic reactions. The various methods available are given in Table 2, although intradermal testing is probably the easiest and most reliable method.12 Atropine has been reported to produce an anaphylactoid reaction10 and an entirely a cell-mediated response. Aguilera et al12 also reported that anaphylaxis due to atropine is rapid

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and the patient developed urticarial rashes, pruritus, nausea and vomiting. The anesthesiologists should be aware of adverse reactions of all the routine drugs used in anesthetic management.14 Conclusion One should perform above tests postoperatively to detect that it is an anaphylaxis and the drug responsible for it. The resuscitation drugs, equipments should be kept ready before administration of any anesthetic drugs. While injecting drugs, one should look for the skin rashes, depth of breathing and should talk to the patient. References 1. Watkins J. Adverse anaesthetic reactions: an update from a proposed national reporting and advisory service. Anaesthesia 1985;40(8):797-800. 2. Fisher MM, More DG. The epidemiology and clinical features of anaphylactic reactions in anaesthesia. Anaesth Intensive Care 1981;9(3):226-34. 3. Watkins J. Anaphylactoid reactions to i.v. substances. Br J Anaesth 1979;51(1):51-60. 4. Stoelting RK. Allergic reactions during anesthesia. Anesth Analg 1983;62(3):341-56. 5. Moudgil GC. Anaesthesia and allergic drug reactions. Can Anaesth Soc J 1986;33(3):400-14. 6. Laxenaire MC, Moneret-Vautrin DA, VervloĂŤt D, Alazia M, FranĂ§ois G. Severe peranesthetic anaphylactic accidents. [Article in French]. Ann Fr Anesth Reanim 1985;4(1):30-46. 7. Laxenaire M, Moneret-Vautrin D, Sigiel M. Allergie et anaesthesie. In: Encyclopedie Medico-chirugicale, Moreau L (Ed.), Editions Techniques: Paris 1979;A10:1-10. 8. Economacos G, Kanakis J. Uncas de sensibilite a L atropine. Anesthesia Analgesia Reanimation 1981;38:748. 9. Fisher M, Baldo B. Anaphylactoid reactions during anaesthesia. In: Clinics in Anaesthesiology. Fisher M (Ed.), W. B. Saunders: London 1984:p.677-92. 10. O'Connor PS, Mumma JV. Atropine toxicity. Am J Ophthalmol 1985;99(5):613-4. 11. Yoshikawa K, Kawahara S. Contact allergy to atropine and other mydriatic agents. Contact Dermatitis 1985;12(1):56-7. 12. Aguilera L, Quevedo M, Casas C. Reaccion anafilactica al droperidol. Revista Espanola de Anestesiologia Y Reanimacion 1984;31:249-52. 13. Le cam B, Tanguy RL, Egreteau JP, les accidents anaphylactoides graves en anesthesia. Seminaux Hopitau 1982:58;2691-5. 14. Kelly JF, Patterson R. Anaphylaxis: course, mechanisms and treatment. JAMA 1974;227(12):1431-6.

Dentistry

Gingival Depigmentation Sharmila Verma*, Meera Gohil**, Vandana Rathwa†

Abstract A smile expresses a feeling of joy, success, sensuality, affection and courtesy and reveals self-confidence and kindness. The harmony of the smile is determined not only by the shape, position and color of the teeth but also by the gingival tissues. Gingival health and appearance are essential components of an attractive smile. Gingival pigmentation results from melanin granules, which are produced by melanoblasts. The degree of pigmentation depends on melanoblastic activity. Although melanin pigmentation of the gingiva is completely benign and does not present a medical problem, complaints of ‘black gums’ are common particularly in patients who have a very high smile line (gummy smile). Different treatment modalities have been reported for depigmentation of gingiva such as bur abrasion, scraping, partial thickness flap, cryotherapy, electrosurgery and laser. In the present case, depigmentation was done with scraping technique, which is simple, effective and yields good results, along with good patient satisfaction.

Keywords: Gingiva, melanin, depigmentation

he gingiva is the most commonly affected intraoral tissue, which is responsible for an unpleasant appearance. Melanin pigmentation often occurs in the gingiva as a result of an abnormal deposition of melanin. Hyperpigmentation of the gingiva is caused by excessive melanin deposition by the melanocytes located mainly in the basal and the suprabasal cell layers of the epithelium. Brown or dark pigmentation and discoloration of gingival tissue can be caused by a variety of local and systemic factors. Systemic conditions such as endocrine disturbances, Albright’s syndrome, malignant melanoma, antimalarial therapy, Peutz-Jeghers syndrome, trauma, hemochromatosis, chronic pulmonary disease and racial pigmentation are known causes of oral melanin pigmentation.1 High levels of oral melanin pigmentation are normally observed in individuals of African, East Asian or Hispanic ethnicity.2,3 Clinical melanin pigmentation of the gingiva does not present a medical problem, although complaints of black gums may cause esthetic problems and

embarassment, particularly if the pigmentation is visible during speech and smiling.4,5 Gingival depigmentation is a periodontal plastic surgical procedure whereby the gingival hyperpigmentation is removed or reduced by various techniques. The first and foremost indication for depigmentation is the patient’s demand for improved esthetics. Various depigmentation techniques have been employed, with similar results. Selection of a technique should be based on clinical experience and the patient's preferences. Removal of gingival melanin pigmentation should be performed cautiously and the adjacent teeth should be protected, since inappropriate application may cause gingival recession, damage to underlying periosteum and bone, delayed wound healing, as well as loss of enamel.6 The present case report introduces a simple and effective surgical depigmentation technique that does not require sophisticated instruments or apparatus, but yet yields esthetically acceptable results. CASE report

*Professor and Head **BDS and PG Student †Senior Lecturer Dept. of Periodontics KM Shah Dental College and Hospital, Sumandeep Vidyapeeth Piparia, Vadodara, Gujarat Address for correspondence Dr Meera H Gohil C/O Dr Navneet G Padhiyar, C-20 A, Medical Campus B/H GG Hospital, Jamnagar Gujarat - 361 008 E-mail: meeragohil5040@gmail.com

A 26-year-old male patient visited the Dept. of Periodontics with the chief complaint of 'black' colored gums (Fig. 1). Oral examination revealed deeply pigmented gingiva from right first premolar to left first premolar in maxilla and right canine to left canine in mandible. The patient requested for any kind of esthetic treatment, which could make his 'black' colored gums look better.

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Dentistry the procedure. After removing the entire pigmented epithelium along with a thin layer of connective tissue with the scalpel, the exposed surface was irrigated with saline. Care was taken to see that all remnants of the pigment layer were removed.

Figure 1. Preoperative picture of black colored gums.

The surgical area was covered with a periodontal dressing. Post-surgical antibiotics (amoxicillin 500 mg, thrice-daily for 5 days) and analgesics (ibuprofen with paracetamol, thrice-daily for 3 days) were prescribed. The patient was advised to use chlorhexidine mouthwash 12-hourly for one week. He was reviewed at the end of one week. The healing process was proceeding normally and patient did not report any discomfort. The patient was asked to continue the chlorhexidine mouthwash for another week. At the end of one month, re-epithelialization was complete and healing was found to be satisfactory. Patient had no complaints of postoperative pain or sensitivity.

Figure 2. Remove of the pigment layer.

At the end of six months, the gingiva appeared healthy and no further repigmentation was seen (Fig. 3). DISCUSSION

Figure 3. Six months postoperative picture.

A scalpel surgery was planned to perform the depigmentation. The entire procedure was explained to the patient and written consent was obtained. A complete medical examination, family history and blood investigations were done to rule out any contraindication for surgery. Local anesthesia was infiltrated in the maxillary anterior region from premolar to premolar and mandibular anterior region canine to canine (lignocaine with adrenaline in the ratio 1:1,00,000 by weight). A Bard Parker handle with a No. 15 blade was used to remove the pigmented layer (Fig. 2). Pressure was applied with sterile gauze soaked in local anesthetic agent to control hemorrhage during

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There are wide variations in gingival color in normal healthy persons. Degree of vascularization, the thickness of the keratinized layer and the amount of the pigment-containing cells will determine the color of the gingiva. Till date very little literature has been published regarding clinical methods of treatment of pigmented gingiva. The techniques that were tried in the past to treat gingival pigmentation include chemical cauterization, gingivectomy,3 scalpel scraping procedure and abrasion of gingiva. The recent techniques of gingival depigmentation in practice are cryotherapy,7,8 free gingival autograft9 and laser10 therapy and these have achieved satisfactory results. Electrosurgery has its own limitations in that its repeated and prolonged use induces heat accumulation and undesired tissue destruction.11 Cryosurgery is followed by considerable swelling and it is also accompanied by increased soft tissue destruction as the depth of penetration can not be controlled. The CO2 laser causes minimum damage to the periosteum and underlying bone and it has unique characteristics of being able to remove a thin layer of epithelium cleanly.12 Although healing of laser wound is slower than scalpel wound, laser wound is a sterile inflammatory reaction. The treated gingiva and mucosa do not

Dentistry need any dressing when it is treated with laser. So reepithelialization will be faster. The use of scalpel technique for depigmentation is the most economical as compared to other techniques, which require more advanced armamentarium. However, scalpel surgery causes unpleasant bleeding during and after the operation, and it is necessary to cover the surgical site with periodontal dressing for 7-10 days. Though the initial result of the depigmentation surgery is highly encouraging, regimentation is a common problem. The exact mechanism of regimentation is not known. Different studies shows variation in the timing for early regimentation. It takes about 1.5-3 years to return to the full clinical baseline regimentation. This variation may be due to the different techniques performed or due to the patient’s race. CONCLUSION The depigmentation procedure was successful and the patient was satisfied with the result. Among the mentioned techniques, we found the scalpel technique to be relatively simple and easy to perform as also cost-effective. Above all, it causes less discomfort and is esthetically acceptable to the patients.

2. Fry L, Almeyda JR. The incidence of buccal pigmentation in caucasoids and negroids in Britain. Br J Dermatol 1968;80(4):244-7. 3. Tamizi M, Taheri M. Treatment of severe physiologic gingival pigmentation with free gingival autograft. Quintessence Int 1996;27(8):555-8. 4. Dummett CO, Sakumura JS, Barens G. The relationship of facial skin complexion to oral mucosa pigmentation and tooth color. J Prosthet Dent 1980;43(4):392-6. 5. Hoexter DL. Periodontal aesthetics to enhance a smile. Dent Today 1999;18(5):78-81. 6. Miserendino LJ, Pick RM. Lasers in dentistry. Quintessence Publishing Co.; Chicago, 1995. 7. Tal H, Landsberg J, Kozlovsky A. Cryosurgical depigmentation of the gingiva. A case report. J Clin Periodontol 1987;14(10):614-7. 8. Yeh CJ. Cryosurgical treatment of melanin-pigmented gingiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86(6):660-3. 9. Dello Russo NM. Esthetic use of a free gingival autograft to cover an amalgam tattoo: report of case. J Am Dent Assoc 1981;102(3):334-5. 10. Atsawasuwan P, Greethong K, Nimmanon V. Treatment of gingival hyperpigmentation for esthetic purposes by Nd:YAG laser: report of 4 cases. J Periodontol 2000;71(2):315-21.

REFERENCES

11. Ozbayrak S, Dumlu A, Ercalik-Yalcinkaya S. Treatment of melanin-pigmented gingiva and oral mucosa by CO2 laser. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;90(1):14-5.

1. Leston JM, Santos AA, Varela-Centelles PI, Garcia JV, Romero MA, Villamor LP. Oral mucosa: variations from normalcy, part II. Cutis 2002;69(3):215-7.

12. Almas K, Sadig W. Surgical treatment of melaninpigmented gingiva: an esthetic approach. Indian J Dent Res 2002;13(2):70-3.

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Unworn Teeth are Less Resistant to Noncarious Lesions Modern lifestyles have put teeth more at risk to noncarious cervical lesions because reduced wear has changed their biomechanics.

Nerve Blocks may Destroy Future Molars in Children A new study has shown that administering alveolar nerve blocks in young children may inadvertently destroy incipient third molars.

ADA/AAOS Look at Joint Implant Infections after Dental Care The first evidence-based clinical practice guideline to be codeveloped by a both the American Academy of Orthopedic Surgeons (AAOS) and the American Dental Association (ADA) suggest that prophylactic antibiotics might not always be needed for routine dental procedures in patients with joint implants, that the jury is still out on the usefulness of topical antibiotics during dental procedures, and that patients with joint implants should be particularly careful about oral hygiene. Source: Medscape

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Diabetology

Tuberous Xanthoma in Diabetes Mellitus: A Case Report sonia Jain*, AP Jain**

Abstract Xanthoma is a deposition of cholesterol in the soft tissues. It is an uncommon presentation of hypercholesterolemia and/or diabetes mellitus (DM). We are reporting a case of 60-year-old female who presented with multiple xanthomas over extensor tendons of both hands and elbows. Her investigations revealed raised triglycerides, very high plasma cholesterol, very lowdensity lipoprotein (VLDL) and low-density lipoprotein (LDL) levels. Fasting and postprandial sugar levels were also increased. A work-up for cardiovascular involvement was normal and biopsy from one of the nodules showed the xanthoma cells.

Keywords: Xanthomatosis, familial hypercholesterolemia, diabetes mellitus

anthomatosis is a cutaneous manifestation of lipidosis in which the plasma lipoproteins and free fatty acids are changed quantitatively and there is accumulation of lipids in large foam cells in the tissues.1 It is associated with abnormalities of cholesterol metabolism.2 There are five types of xanthomas based on clinical presentation. We are reporting here a case of tuberous xanthoma, which occurs due to familial heterozygous hypercholesterolemia (type II a) and usually presents as nodules localized to extensor surfaces of elbows, knees, knuckles and buttocks.3 Familial heterozygous hypercholesterolemia occurs as a result of inheritance of single abnormal allele for the low-density lipoprotein (LDL) receptor.3 Fredrickson classified familial hyperlipidemia into five main types based on the changes in plasma lipoprotein spectrum and other associated changes.4 CASE REPORT

of their unavailability. On examination, she had an average built with height of 145 cm and weight of 60 kg. Her body mass index (BMI) was 17.4. Her blood pressure was 140/90 mmHg and her other vital parameters were normal. On cutaneous examination, multiple yellowish colored papules and nodules were found on the dorsum of fingers of both hands at interphalangeal joints (Fig. 1) and extensor aspect of both elbows (Fig. 2). Examination of the eyes revealed sclerotic changes in the retinal vessels and arcus corneae. Hair, nail, mucosae as well as palms and soles were normal. Laboratory investigations like complete blood count (CBC), erythrocyte sedimentation rate (ESR), blood sugar, lipid profile and skin biopsy were carried out. She was not taking any medications before coming to the hospital. She was found to have raised blood sugar and lipid levels. Her cholesterol was increased 6-folds (Table 1).

A 60-year-old female patient presented with history of gradually enlarging nodules over both hands and elbows since one year, not associated with pain or itching. The family history was insignificant and none of the family members including parents had similar lesions. However, they could not be investigated because

*Associate Professor Dept. of Skin and VD, MGIMS, Sewagram, Wardha, Maharashtra **Associate Professor Dept. of Medicine, MGIMS, Sewagram, Wardha, Maharashtra Address for correspondence Dr Sonia Jain A-13, Dhanvantri Nagar, MGIMS, Sewagram, Wardha, Maharashtra - 442102 E-mail: soniapjain@rediffmail.com

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Figure 1. Subcutaneous nodules over the extensor aspect of hands.

Diabetology

Figure 2. Xanthomas over the extensor aspect of the elbows.

Table 1. Blood Investigations Patient’s value Normal value Total cholesterol (mg/dl)

923

150-250

LDL cholesterol (mg/dl)

314

100-160

HDL cholesterol (mg/dl)

255

30-60

VLDL cholesterol (mg/dl)

354

10-30

Triglycerides (mg/dl)

231

50-150

FBS (mg/dl)

159

80-120

PP2BS (mg/dl)

234

180-200

FBS: Fasting blood sugar; PP2BS: 2-hour postprandial blood sugar.

Electrocardiogram (ECG), treadmill test (TMT) and echocardiography were done to look for the cardiovascular effects of hypercholesterolemia and they proved to be normal. The chest X-ray was normal, while that of hands and elbows showed multiple soft tissue swellings corresponding to cutaneous lesions and normal underlying bones. Biopsy from one of the nodules showed normal epidermis and aggregates of xanthoma cells separated by fibrocollagenous bundles in the dermis. DISCUSSION Xanthomas may be seen either as a primary disorder or secondary to various acquired systemic diseases like hypothyroidism, biliary cirrhosis, diabetes mellitus, nephrotic syndrome, monoclonal gammopathy and intake of drugs like b-blockers, diuretics.5 DM is a common cause of hypertriglyceridemia and the eruptive xanthomas may be the first sign of untreated DM.6 Dyslipidemias in DM usually occur in young insulinresistant diabetics. Insulin is necessary for the normal clearing action of lipoprotein lipase on triglycerides. In this case too, DM was detected for the first time. The decreased lipoprotein lipase activity in insulindependent diabetes results in the accumulation of

serum triglycerides, the levels of which are occasionally highly elevated to produce eruptive xanthomas.1 Frequently, the underlying problem is uncontrolled diabetes. Xanthomas occur anywhere on the body, but particularly on the extensor surfaces of the limbs and the buttocks. The papules are discrete and domeshaped but may coalesce to form plaques and nodules when they are called tuboeruptive. Tuboeruptive lesions occur mainly over the elbows.3 Tuberous xanthomas are found localized to the extensor surface of the elbows, knees, knuckles and buttocks.3 Plane xanthomas typically develop in skin folds, especially in the palmar creases (xanthoma striatum palmare) and on the upper eyelids (xanthelasma palpebrum).3 Eruptive xanthoma variant presents with sudden onset of crops of small, pruritic, red-yellow papules on an erythematous base, most commonly over buttocks, shoulders and extensor surfaces of extremities; may spontaneously resolve over weeks.2 Tendinous xanthomas are asymptomatic, slowly enlarging subcutaneous nodules attached to tendons, ligaments, fascia and periosteum with normal overlying skin.2 Extensor tendons of the hands, feet including Achilles tendons are involved more frequently. Our patient was treated for DM with tablet metformin 500 mg twicedaily and for altered lipid levels with atorvastatin 40 mg and fenofibrate 160 mg once-daily with dietary restrictions of cholesterol and saturated fatty acids. REFERENCES 1. Errors in metabolism. In: Andrew’s Diseases of the Skin: Clinical Dermatology. 9th edition, James, Berger, Elston, Odom (Eds.), WB Saunders Company: Philadelphia 2000:p.648-81. 2. Black MM, Gawkrodger DJ, Seymour CA, Weismann K. Metabolic and nutritional disorders. In: Textbook of Dermatology, Champion. 6th edition, Burton, Burns, Breathnach (Eds.), Blackwell-Science: Oxford 1998:p.2577-677. 3. White LE. Xanthomatoses and lipoprotein disorders. In: Fitzpatrick’s Dermatology in General Medicine. 7th edition, Wolff, Goldsmith, Katz, Gilchrest, Paller, Leffell (Eds.), McGraw-Hill: New York, NY 2008:p.1272-80. 4. Mahajan VK, Sharma NL, Sood S. Xanthoma tendinosum and familial hypercholesterolemia. Indian J Dermatology 2003;48(2):116-8. 5. Pandhi D, Grover C, Reddy BS. Type IIa hyperlipoproteinemia manifesting with different types of cutaneous xanthomas. Indian Pediatr 2001;38(5):550-3. 6. Binić I, Janković A. Eruptive xanthomas associated with diabetes mellitus. Chinese Medical Journal 2009;122(17):2074-5.

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ENT

Scalpel Cautery Adenotonsillectomy Done in a Case of Crouzonâ&#x20AC;&#x2122;s Syndrome Sudhir M Naik, Sarika S Naik

Abstract Background/Objectives: Crouzon syndrome is characterized by premature closure of the cranial sutures, midface hypoplasia, orbital deformities and other associated abnormalities. Children with Crouzon syndrome frequently have obstructive sleep apnea due to the underdevelopment of the midface. Setting: Dept. of ENT, Head and Neck Surgery and Anesthesia, KVG Medical College, Sullia. Case report: A 12-year-old boy of Crouzon syndrome with chronic adenotonsillitis was managed by adenotonsillectomy under general anesthesia by scalpel cautery method. The boy responded well to surgery and the mild sleep disorder disappeared within a week uneventfully. Conclusion: Sleep disorders in this condition can be treated by improving the airway by selective procedures like midface advancement, mandibular expansion, adenotonsillectomy, uvulopalatopharyngoplasty, anterior tongue reduction and endoscopic tracheal granuloma excision.

Keywords: Crouzon syndrome, adenotonsillectomy, craniosynostosis, proptosis

rouzon syndrome is a rare autosomal dominant skeletal disorder caused by multiple mutations in the fibroblast growth factor receptor 2 (FGFR-2) gene.1 Paternal age older than 35 years is associated with the 60% of all new mutations leading to this condition.1 It occurs in one of every 25,000 live births and accounts for 5% of cases of craniosynostosis.1

Crouzon syndrome has two variants. The classic variant is caused by a mutation of the FGFR-2 gene, located on chromosome 10 and the second variant, notable for the presence of abnormal skin pigmentation called acanthosis nigricans, is the result of a mutation in FGFR-3, located on chromosome 4.2 Nucleotide alterations causing amino acid substitutions at the FGFR-2 gene on chromosome 10 lead to the Crouzon phenotype.1 It is commonly inherited as an autosomal dominant trait, with complete penetrance and variable expressivity,3 but 30-60% of cases are sporadic and represent fresh mutations.4 It accounts for approximately 4.8% of all cases of craniosynostosis, with a prevalence of approximately 1/25,000 live births worldwide.3,5 Clinical findings include brachycephalic

Flat No. 140, Nisarga Keerthana Apartments, Beside Hotel Keethana International After Narayana Hrudayalaya Chandapura Hosur Main Road, Bangalore, Anekal Taluq Bangalore - 560 099, Karnataka E-mail: sud223@gmail.com

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craniosynostosis, significant hypertelorism, proptosis, maxillary hypoplasia, beaked nose and possibly, cleft palate. Intracranial anomalies include hydrocephalus, Chiari I malformation and hindbrain herniation.1 It is characterized by premature closure of the cranial sutures, midface hypoplasia, orbital deformities and other abnormalities.3 The diagnosis is based on clinical findings and radiological examination.3 Early recognition and specific therapeutic interventions are essential to guide the growth and development of the craniofacial region.3 Pathology of the ear and cervical spine is common.2 Infants with Crouzon syndrome do not have anomalies of the hands and feet as do infants with Apertâ&#x20AC;&#x2122;s syndrome.2 The abnormal skull shape is usually noted in the newborn period although occasionally, it may be detected either prenatally or not until later in infancy. The appearance of an infant with Crouzon syndrome can vary in severity depending on the order and rate of the fusion of the sutures.3 Despite tremendous advances in the establishment of inheritance mode of this condition, prevention and treatment, it remains a significant cause of morbidity worldwide.3 It is important to be aware of the syndrome so as to impart better care.3 Genetic testing and individual study of each patient with suspected syndrome are essential for early diagnosis and management and to differentiate the condition from other syndromic and nonsyndromic craniosynostosis.3

ENT We report a rare case of Crouzonâ&#x20AC;&#x2122;s syndrome in a 12-year-old boy with characteristic features of maxillary hypoplasia, proptosis with minimal cranial deformity and chronic adenotonsillitis. Case report A 12-year-old boy of normal intelligence presented to the Dept. of ENT, Head and Neck Surgery, KVG Medical College, Sullia with history of sore throat and difficulty in swallowing since one week with similar episodes since three years. No difficulty in speech but occasional difficulty in swallowing due to enlarged tonsils was reported. He had one elder brother with no features of the disease. None of the parents, or other family members had similar facial features. At the time of his birth, father was 37 years and his mother 29-year-old and they had a nonconsanguineous marriage. History from his parents revealed that his facial features were different from other children of his age. They had noticed the gradual bulging of his eyes after the age of one year. Parents complained of chronic mouth breathing and snoring while sleeping with chronic denasal speech. There was no family history of similar symptoms or any other congenital abnormality. His developmental milestones were normal, but he appeared smaller than other children of his age. Clinical examination showed the cranial vault was regular with no undue prominence. No brachycephaly, flatness of forehead or occiput was seen. The frontal hairline was not low-set. No ridging of the skull was seen in regions of coronal, lambdoid sutures and anterior to the vertex. Midface flattening with maxillary hypoplasia and a relatively large mandible was seen. The upper lip was small compared to the everted lower lip. Ophthalmologic evaluation revealed shallow orbits, hypertelorism, bilateral proptosis, mild exotropia, no papillary edema or optic atrophy. His nasal bridge was normal with right septal deviation. His nose was slightly pointed with dorsal hump with normally set ears with normal hearing. The hands and feet were normal with no other abnormality seen. Oral cavity showed U-shaped dental arches with a high-arched palate with hard and soft palates being normal with normal oral hygiene. His dentition was normal with no caries. There was no evidence of temporomandibular dysfunction. Orthopantomographic view confirmed the clinical findings. A retruded maxilla with a relatively large mandible was seen on X-ray lateral view of the skull. The widely spaced orbits, hypoplastic maxilla and

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Figure 1. Proptosis and nasal deformity with no maxillary prominence.

Figure 2. Protrusion of the mandible with maxillary flatness.

Figure 3. No deformity of the palate but a large tongue compared to the mouth cavity.

zygoma are due to early fusion of coronal and lambdoid sutures. Cardiovascular, respiratory and abdominal examinations were normal. Routine hematological and biochemical tests showed hemoglobin (Hb) 12.8 g/dl, erythrocyte sedimentation rate (ESR) 10 mm/hour and total leukocyte count (TLC) 7,400 cells/mm3 with polymorphs 57%, lymphocytes 36% and eosinophils

ENT

Figure 6. Normal cranial vault and ear with maxillary hypoplasia.

Figure 4. Normal dentition with maxillary hypoplasia. Figure 7. Normal X-ray of the hand and cranial vault with maxillary hypoplasia.

Discussion

Figure 5. Normal chest X-ray and maxillary hypoplasia.

7%. Blood group was O-positive; urine tests were within normal limits. Based on the above clinical and radiological findings and in the absence of hand and feet anomalies, a diagnosis of Crouzon syndrome was made. Cardiovascular and respiratory systems were normal on pre-anesthetic examination. He was accepted for adenotonsillectomy in ASA II under general anesthesia. The surgery was done in 45 minutes under scalpel cautery method.

Crouzon syndrome was first described by Octave Crouzon in a mother and son with the characteristic triad of calvarial deformities, facial anomalies and proptosis.6 Mutation of the FGFR gene is also responsible for other craniosynostosis such as Apert’s, Pfeiffer’s, Jackson-Weiss and Saether-Chotzen’s syndromes.7 Rarely, acanthosis nigricans may coexist with Crouzon syndrome and is caused by mutation in the transmembrane region of the FGFR-3 gene.8 The sporadic cases are postulated to be associated with advanced paternal age; some investigators have found that this mutation is more common in the sperm of older men.9 Due to variability of phenotypic expression, some patients exhibit complete phenotypic penetrance, whereas other family members may appear normal and still carry a Crouzon mutation as seen in our patient.10 Crouzon’s syndrome has no racial or sex predilections.10 The craniosynostosis of sagittal or

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809

ENT metopic types are more predominance in boys, while coronal craniostenosis is more common in girls. The condition is usually detected in the first year of life and sometimes congenital forms are seen at birth due to synostosis in the uterus itself.11 The coronal sutures usually close first and eventually all cranial sutures close early. The coronal and sagittal sutures are most commonly involved. As the skull grows in planes perpendicular to the cranial sutures, premature suture closure causes skull growth to cease in the plane perpendicular to the closed suture and to proceed parallel to the suture.11 The skull shape becomes asymmetric, with the shape depending on the sutures involved. The characteristic cranial shapes are brachycephaly (disproportionate shortness of the head), scaphocephaly (boat-shaped head), trigonocephaly (triangle-shaped head) or, in severe disease, cloverleaf skull deformity.12 The facial malformations consist of hypoplasia of the maxilla with mandibular prognathism, high-arched palate, bilateral palatal swelling, rarely cleft palate, exaggerated facial angle; the nose appears prominent and pointed (beak-like nose), recalling a ‘parrot beak’ due to short and narrow maxilla.13 Conductive hearing loss and ear infections are common due to middle ear deformities.11 Upper airway obstruction may occur due to midfacial hypoplasia and a narrow epipharynx.11 Ocular abnormalities such as bilateral ocular proptosis due to extremely shallow orbits and hypertelorism due to decrease in the growth of sphenozygomatic and sphenotemporal sutures are seen.14 Optic atrophy is frequently seen in 30-80% of patients. Other ocular abnormalities include divergent strabismus, conjunctivitis or exposure keratoconjunctivitis, as well as unexplained loss of visual accuracy.15 Mental ability and psychomotor development is generally within the normal limits. However, increased intracranial pressure can lead to mental retardation.11 Sometimes headache and convulsions are also seen.11 A thorough clinical, radiological and genetic analysis is required for early recognition and diagnose of this syndrome.11 X-rays show obliterated sutures, hypoplastic maxilla with shallow orbits, shortened cranial fossa, enlarged hypophyseal cavity and small paranasal sinuses.13 Prominent cranial markings of the inner surface of the cranial vault may be seen as multiple radiolucencies appearing as depressions (so called digital impressions) resulting in the hammered silver (beaten metal/copper beaten) appearance.13

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A copper beaten skull indicating internal remodeling of the calvaria due to an increase in intracranial pressure as a result of premature cranial suture fusion may be seen.11 On spine radiography, abnormal craniocervical junction, butterfly-shaped vertebrae and fusion of the cervical vertebrae (C2-C3 and C5-C6) may be visible.11 X-ray examination of the metacarpal bones and fingers may reveal slight achondroplasia.13 Ventriculomegaly is frequently noticed in central nervous system imaging, but is usually asymptomatic and does not require treatment.16 Corpus callosum agenesis and optic atrophy are rarely seen on magnetic resonance imaging (MRI).16 Three-dimensional ultrasonography and MRI aid early detection and diagnosis of fetal malformation.17 Prenatal diagnostic testing for a known FGFR gene mutation is a reasonable option for couples at risk for having a child with Crouzon syndrome due to germline mosaicism.17 The syndrome must be differentiated from simple craniosynostosis and other syndromic craniosynostosis.18 Once craniosynostosis is seen radiographically, it is important to determine whether it occurred because of abnormal biology of the cranial suture, possibly caused by an FGFR mutation (primary craniosynostosis).18 The features of Apert’s syndrome are very similar but are characterized by craniosynostosis, midface hypoplasia and symmetric syndactyly of the hands and feet.19 Differential diagnosis is also made with the other syndromes associated with features of craniosynostosis such as Pfeiffer’s syndrome, SaethreChotzen’s syndrome and Jackson-Weiss syndrome.19 All these syndromes involve craniofacial abnormalities as well as other abnormalities, including the hands and feet.19 The management requires a multidisciplinary approach to prevent early fusion of craniofacial suture, thus minimizing intracranial pressure and secondary craniofacial deformities.19 Early release of the synostotic sutures of the skull allows adequate cranial volume for brain growth.19 Skull reshaping may need to be repeated as the child grows.19 Depending on the severity of the deformity, midfacial advancement and jaw surgery can be done to provide adequate orbital volume and correcting the occlusion for appropriate function.19 The prognosis depends on the severity of the malformation and the timing of intervention. Patients usually have a normal lifespan.19 In a study of 244 children 20% of these children with syndromes

ENT with respiratory distress required tracheostomy.20 Craniofacial synostosis patients (Crouzon, Pfeiffer or Apert syndrome) had the highest rate of tracheotomy (48%), mandibulofacial dysostoses patients (Treacher Collins or Nager syndrome) being the next highest rate (41%) and patients with oculo-auriculo-vertebral sequence were less likely to undergo tracheotomy (22%).20 Children with craniosynostosis rarely required a surgical airway, unless there was marked associated facial dysmorphism (1%).20 The presence of a cleft palate correlated with reduced risk for tracheotomy. We performed adenotonsillectomy to improve the snoring and sleep disorder problem. Other procedures done to improve airway are midface advancement, mandibular expansion, uvulopalatopharyngoplasty, anterior tongue reduction and endoscopic tracheal granuloma excision.20 Conclusions Crouzon syndrome can present with a wide range of clinical features. The affected boy in this case presented with varying degrees of craniosynostosis, ocular proptosis, hypertelorism, hypoplastic maxilla and chronic tonsillitis. The diagnosis is usually based on clinical and radiographic findings of the craniofacial region. Molecular genetic testing for mutations in the FGFR-2 gene may be useful adjuncts, particularly when prenatal detection in subsequent family members is desired. Sleep disorders in this condition can be treated by improving the airway by selective procedures like midface advancement, mandibular expansion, adenotonsillectomy, uvulopalatopharyngoplasty, anterior tongue reduction and endoscopic tracheal granuloma excision. References 1. Corde Mason A, Bentz ML, Losken W. Craniofacial syndromes. In: Atlas of Pediatric Physical Diagnosis. Zitelli BJ, Davis HW (Eds.), 4th edition, Mosby: St. Louis, 2002:p.803-17. 2. Reardon W, Winter RM, Rutland P, Pulleyn LJ, Jones BM, Malcolm S. Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. Nat Genet 1994;8(1):98-103.

5. Kaur H, Waraich HS, Sharma CM. Crouzon syndrome: a case report and review of literature. Indian J Otolaryng Head Neck Surg 2006;58(4):381-2. 6. Crouzon O. Dysostose cranio-faciale hereditaire. Bull Soc Med Hop Paris 1912;33:545-55. 7. Preising MN, Schindler S, Friedrich M, Wagener H, Golan I, Lorenz B. On the effect of mutations of the fibroblast growth factor receptors as exemplified by three cases of craniosynostoses. Klin Monbl Augenheilkd 2003;220(10):669-81. 8. Meyers GA, Orlow SJ, Munro IR, Przylepa KA, Jabs EW. Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans. Nat Genet 1995;11(4):462-4. 9. Glaser RL, Jiang W, Boyadjiev SA, Tran AK, Zachary AA, Van Maldergem L, et al. Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome. Am J Hum Genet 2000;66(3):768-77. 10. Cohen MM Jr. Crouzon syndrome. In: Craniosynostosis: Diagnosis, Evaluation, and Management. 2nd edition, Cohen MM Jr (Ed.), Oxford University Press: New York 2000:p.361. 11. da Silva DL, Palheta Neto FX, Carneiro SG, et al. Crouzon’s syndrome: literature review. Intl Arch Otorhinolaryngol, São Paulo 2008;12:436-41. 12. Developmental defects of the oral and maxillofacial region. In: Oral and Maxillofacial Pathology. 2nd edition Neville BW, Damm DD, Allen CM, Bouquet JE (Eds.), Elsevier Publishers 2004:p.40. 13. Shafer WG, Hine MK, Levy BM. A Textbook of Oral Pathology. 5th edition, Elsevier Publishers 2006:p.984-6. 14. Ahmed I, Afzal A. Diagnosis and evaluation of Crouzon syndrome. J Coll Physicians Surg Pak 2009;19(5):318-20. 15. Abdallah AM. A severe form of Crouzons syndrome: clinical and radiological correlation. Saudi J Ophthalmol 2003;17:183-5. 16. Gupta AK, Koley S, Choudhary S, Bhake A, Saoji V, Salodkar A. A rare association of acanthosis nigricans with Crouzon syndrome. Indian J Dermatol Venereol Leprol 2010;76(1):65-7. 17. Jaczyńska R, Kutkowska-Kaźmierczak A, Obersztyn E, Niemiec KT, Leibschang J, Ceran A, et al. Prenatal diagnosis of Crouzon syndrome - actual diagnostic possibilities. Ginekol Pol 2006;77(2):138-45. 18. Tsai FJ, Yang CF, Wu JY, Tsai CH, Lee CC. Mutation analysis of Crouzon syndrome and identification of one novel mutation in Taiwanese patients. Pediatr Int 2001;43(3):263-6.

3. Bowling EL, Burstein FD. Crouzon syndrome. Optometry 2006;77(5):217-22.

19. Katzen JT, McCarthy JG. Syndromes involving craniosynostosis and midface hypoplasia. Otolaryngol Clin North Am 2000;33(6):1257-84, vi.

4. al-Qattan MM, Phillips JH. Clinical features of Crouzon’s syndrome patients with and without a positive family history of Crouzon’s syndrome. J Craniofac Surg 1997;8(1):11-3.

20. Sculerati N, Gottlieb MD, Zimbler MS, Chibbaro PD, McCarthy JG. Airway management in children with major craniofacial anomalies: Laryngoscope 1998;108(12): 1806-12.

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Endoscopic Diagnosis, Screening and Surveillance and Treatment of Barrett’s Esophagus: An Overview Praveen Kumar Yadav*, Teng Fei Chen**, Zhanju Liu†

Abstract Barrett’s esophagus (BE) is an acquired condition in which the squamous epithelial lining of the lower esophagus is replaced by a columnar epithelium due to chronic gastroesophageal reflux. The prevalence of BE has ranged from 0.9% to 4.5%. The rate of progression from BE to esophageal adenocarcinoma is 0.5% per patient-year. Human studies show that the reflux of bile parallels acid reflux and increases with the severity of gastroesophageal reflux disease (GERD), being most marked in BE. However, recent ex vivo studies suggest that pulses of acid reflux may be more important than bile salts in the development of dysplasia or adenocarcinoma in Barrett’s epithelium. The diagnosis of BE can be suspected when, during endoscopic examination, columnar epithelium is observed to extend above the gastroesophageal junction (GEJ) into the tubular esophagus. Although, guidelines for the diagnosis, surveillance and management of BE were published, the main goal in the management of premalignant condition would be the permanent elimination of Barrett’s mucosa. Current therapeutic options are limited or still in the investigational stages. This review summarizes the endoscopic diagnosis, screening, surveillance and introduces endoscopic ablative modalities currently used.

Keywords: Argon plasma coagulation, Barrett’s esophagus, endoscopic mucosal resection, gastroesophageal reflux disease, multipolar electrocoagulation

arrett’s esophagus (BE) is the condition in which any extent of metaplastic columnar epithelium that predisposes to cancer development replaces the stratified squamous epithelium that normally lines the distal esophagus,1 which gives a red appearance to the esophagus on endoscopic examination. Many etiological factors are involved in the development of BE, such as gastroesophageal reflux disease (GERD), with inflammatory stress leading to metaplastic transformation of the mucosa. Advanced age, male sex, white race, symptoms of reflux and obesity are the risk factors for BE. Upper endoscopy is required for diagnosis, which is based on initial endoscopic investigation and histopathologic examination of specimens obtained from biopsy of the endoscopically visible Barrett’s segment. The affected segment may extend to variable

lengths. BE that is more commonly seen among Asian populations is short-segment (<3 cm), while in Western populations a long segment (>3 cm) type is mostly seen. Societal guidelines generally have recommended endoscopic surveillance for patients with BE at intervals of 3-5 years for patients who have no dysplasia, six months to one year for those found to have low-grade dysplasia (LGD) and every three months for patients with high-grade dysplasia (HGD) who receive no ablation therapy.2 Screening a high-risk group such as men with GERD will result in the detection of more patients with BE, many of whom are asymptomatic. BE occurs more often in men than women. The male-tofemale ratio is approximately 2:1.3 The aim of this literature review is to summarize the endoscopic diagnosis, screening, surveillance and introduces endoscopic ablative modalities currently used. Prevalence of BE

*MBBS, MD, Zhengzhou University, China **BM, Tongji University, China †MD, Henan Medical University, China University of Leuven,Belgium Address for correspondence Prof. Zhanju Liu Dept. of Gastroenterology, The Shanghai Tenth Peoples Hospital, Tongji University No. 301, Yanchang Middle Road, Shanghai - 200 072, China E-mail: zhanjuliu@yahoo.com

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The prevalence of BE in the general US population is not known; the prevalence of GERD is increasing both in the West and in Asia and this may justify strategies for prevention and early detection of BE. Hiatal hernia is also associated with the presence of BE.4 In one of the population-based studies conducted in Sweden,

Gastroenterology BE was diagnosed in 1.6% of 3,000 study participants.5 Studies have reported inverse associations between the presence of BE and consumption of red wine, Helicobacter pylori (HP) infection and black race.6 Esophageal adenocarcinoma has been estimated to develop in about 0.5-1.0% of patients with BE annually7 and is now the most rapidly increasing cancer in the Western world. The incidence of adenocarcinoma in patients with BE increases with the degree of dysplasia from approximately 0.5% per year8 in nondysplastic BE to as high as 15-20% per year in subjects with HGD.9,10 BE itself does not cause symptoms. The extent of dysplasia is usually characterized by pathologists as mild or LGD, and severe or HGD. Current techniques for endoscopic monitoring of the disease represent a large cost burden, the value of which has been called into question.11 Diagnosis Individuals who have experienced acid reflux symptoms for a number of years should undergo an upper endoscopy exam to determine if they have BE. BE is marked by the presence of columnar epithelia in the lower portion of esophagus, replacing the normal squamous cell epithelium that is metaplasia. This metaplasia confers an increased risk of adenocarcinoma.12 The line at which the columnar epithelium transitions to the squamous epithelium (i.e., the squamocolumnar junction) is known as the Z-line. Normally, the Z-line corresponds to the gastroesophageal junction (GEJ). In BE, the Z-line is displaced proximally relative to the GEJ. BE is diagnosed by endoscopy and histology. An endoscopy procedure is done to look at the lining of the esophagus and take biopsies to examine samples of suspect tissue. The biopsy is examined in a lab to see whether the normal squamous cells have been replaced with Barrett’s cells.13 Long-segment BE measures ≥3 cm from the GEJ, while short-segment BE is <3 cm from the GEJ.5 More metaplasia would predispose to more cancer, and one study14 has shown this to be the case. On histopathologic examination, intestinal metaplasia can be identified by the presence of goblet cells on biopsy of the esophageal mucosa. There may be two types of metaplastic columnar cells: Gastric that are similar to those in the stomach, which is not technically BE or colonic that are similar to cells in the intestines. Colonic-type metaplasia is the type of metaplasia associated with risk of malignancy in genetically susceptible people.

Histochemical stain Alcian blue (pH 2.5) is used to distinguish true intestinal-type mucins from their histologic mimics. Recently, immunohistochemical analysis with antibodies to CDX-2 (specific for mid and hindgut intestinal derivation) has also been utilized to identify true intestinal-type metaplastic cells. It has been shown that the protein AGR2 is elevated in BE15 and it can be used as a biomarker for distinguishing BE from normal esophageal epithelium.16 After the initial diagnosis of BE, the affected people undergo annual surveillance to detect changes that indicate higher risk to progression to dysplasia. Screening and surveillance for BE Screening and surveillance for BE remain very controversial topics. Screening refers to the initial endoscopic examination performed in subjects for the detection of BE and/or esophageal adenocarcinoma while surveillance is the continued observation of patients with BE by serial endoscopy for the detection of dysplasia and/or early cancer. There are several challenges to screening for BE such as inability to predict who has BE prior to endoscopy, the lack of evidence-based criteria, the invasiveness and expense of endoscopy and the increasing documentation of a subgroup of patients with BE who lack reflux symptoms. Predictors included age >40,17 heartburn,17,18 long duration GERD symptoms (≥13 years) and male gender.18 Histological confirmation of disease varies with the length of columnar appearing mucosa identified at endoscopy, with suspected short-segment disease confirmed in only about 25% of cases and longsegment disease confirmed in 44-80% of cases.19 More than 20% of patients without confirmation of intestinal metaplasia at initial endoscopy are found to have it at later endoscopy probably because of sampling error or interim development of intestinal metaplasia after the first examination.20 A retrospective study of endoscopic and pathology reports from 15 hospitals in The Netherlands revealed that adherence to the Seattle protocol was 79% for cases in which Barrett’s metaplasia involved only upto 5 cm of the distal esophagus but diminished with increasing extent of metaplasia to the point that there was only 30% adherence among cases with metaplasia involving 10-15 cm of the esophagus.21 Esophageal biopsy specimens taken for evaluation of BE and who had endoscopy reports that documented the extent of esophageal columnar lining was found in only 51% of cases. As in the previous study, adherence to the protocol varied inversely with the extent of Barrett’s metaplasia.22

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Gastroenterology Streitz et al23 studied 77 patients treated for esophageal adenocarcinoma. Among them, the cancers were found in 19 patients during surveillance endoscopies performed, while 58 patients had symptoms of esophageal cancer, and BE was first diagnosed when their tumors were resected. Fountoulakis et al24 studied a cohort of consecutive patients who underwent esophagectomy for HGD or adenocarcinoma in BE and showed 1- and 3-year survival rates for the surveillance and nonsurveillance groups of 88% versus 67% and 80% versus 31%, respectively. Corley et al25 studied 589 patients with adenocarcinoma of the esophagus or gastric cardia diagnosed during 1990-1998. Only 23 patients were known to have had BE for at least six months before the cancer was diagnosed and 15 had their tumors discovered during surveillance endoscopy. In a more recent analysis, Cooper et al26 included 2,754 patients with a new diagnosis of esophageal adenocarcinoma. Undergoing an endoscopy three years to six months before the diagnosis of cancer was associated with an improvement in median survival from seven months (for patients with no prior endoscopy) to 11 months. In a case-control study, Kearney et al27 found that a group of 245 patients who had GERD and adenocarcinoma of the esophagus or gastric cardia were significantly less likely to have undergone endoscopy in the 1-8 years before the index date than 980 control subjects (matched by age, sex and race) who had GERD without cancer (adjusted odds ratio [OR], 0.66; 95% confidence interval [CI], 0.45-0.96). The American College of Gastroenterology (ACG) guidelines state that “patients with chronic GERD symptoms are those who are most likely to have BE and should undergo upper endoscopy”.28 If BE is detected as part of surveillance for precancerous cell changes called dysplasia, an endoscopic biopsy should be done every 2-3 years. If intraepithelial neoplasia is found in the Barrett’s epithelium, appropriate intervention, with follow-up surveillance at appropriate time-intervals is generally recommended.12 It is recommended that 4-quadrant biopsy samplings of the Barrett’s epithelium are taken at 1- to 2-cm intervals along the entire segment of affected esophageal tissue. Surveillance procedures call for periodic examinations, with the frequency dictated by the degree of dysplasia observed.1,7 Patients with BE with dysplasia should undergo surveillance endoscopy every six months for LGD or every three months for HGD as long as dysplasia was noted at least once during the preceding 12 months.29 It has been suggested that screening should focus on patients with GERD who have risk factors for BE, such as male

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sex, white race, age >50 years and a long history of symptoms (>5 years). Endoscopic surveillance programs have been established in an effort to diagnose cancer at an early stage in patients with BE. The numbers of published case-control and cohort studies have shown that endoscopic surveillance is significantly associated with both an earlier stage of esophageal adenocarcinoma at diagnosis and improved survival.30 In a survey in UK by Mandal et al, only 76% of respondents considered that surveillance was worthwhile. In those who considered surveillance worthwhile, 83% used sub-selection based on age, length of Barrett’s or presence of ulcer or stricture.30 Although, no randomized, controlled trials have evaluated the efficacy of surveillance, and also it is not clear whether surveillance reduces the mortality from esophageal cancer, most of the major gastroenterological societies and published guidelines recommend surveillance of patients with BE. There are several factors, which expected benefits of current surveillance strategies such as the low overall incidence of cancer in BE patients, the absence of a previous diagnosis of BE in the majority of patients with esophageal adenocarcinoma and difficulties in the diagnosis of dysplasia, which is a high missing rate on evaluation of random biopsy specimens and high variation among pathologists in the interpretation of biopsy findings.31,32 Recent studies suggest an annual risk of cancer of 0.5% or less. Sharma et al33 observed the incidence of cancer to be one case in 212 patient-years of follow-up (0.5% per year). A meta-analysis34 shows the incidence rates for esophageal adenocarcinoma to range from 0.6% to 1.6% per year in patients with LGD. Esophageal adenocarcinoma development rate is high among patients with HGD, with an estimated incidence of 6.6 cases per 100 patient-years (95% CI, 4.9-8.2) in a recent meta-analysis.35 In a randomized crossover study36 of 121 patients undergoing endoscopy for screening and surveillance of BE, the prevalence of disease was similar between conventional endoscopy (26%) and unsedated small-calibre endoscopy (30%). In a singlecenter prospective study37 of 90 patients undergoing screening or surveillance for BE, capsule endoscopy was 67% sensitive and 84% specific for identification, diagnosing 14 of 21 cases who were confirmed by biopsy. Somewhat improved operating characteristics of capsule endoscopy were seen in 89 patients by French investigators.38 Recently, enhanced optical imaging techniques i.e., high-resolution, white-light endoscopy, magnification endoscopy, chromoendoscopy, narrow-

Gastroenterology band imaging (electronic chromoendoscopy), autofluorescence imaging, confocal microscopy have been suggested to improve the efficiency and accuracy of endoscopic surveillance. Most of these techniques have not been directly compared with standard endoscopy, but use of narrow-band imaging and confocal laser endomicroscopy suggest a high rate of accuracy (85-92%) in the diagnosis of neoplasia in patients with BE.39,40 The cost-effectiveness of endoscopic screening and surveillance is still unknown, and it depends upon poorly described factors such as the accuracy of the test to diagnose BE, the risk of cancer in patients with the condition and the cost of endoscopy and histological analysis.41 One analysis suggested that although one screening endoscopy was highly cost-effective, subsequent surveillance endoscopies in patients whose biopsies showed only BE with no dysplasia were very cost-ineffective, adding only a few extra days of life expectancy at an extra cost of thousands of US dollars.42 In a prospective double-blind study of 33 patients, the technique had an accuracy of 78% for the detection of dysplasia in patients with BE.43 In a study of 63 patients with BE and associated neoplasia, changes were detected with 98.1% and 92.9% sensitivity and 94.1% and 98.4% specificity, respectively (96.8% and 97.4% accuracy, respectively).40. Endoscopic treatment of BE Endoscopic therapies can be further subdivided into tissue-acquiring and nontissue-acquiring modalities.

Multipolar Electrocoagulation It is a safe, effective method to ablate BE over long-term in combination with acid suppression, according to findings from a 10-year follow-up study. Allison et al44 treated 166 patients who were recruited for the study; 139 completed at least 10 years of follow-up. Complications developed in <5% of patients. Recurrent BE occurred in <5% of patients. No adenocarcinoma or HGD of the esophagus developed in any of the patients. Sharma et al45 compared Argon plasma coagulation (APC) and mulipolar electrocoagulation (MPEC) for ablation of nondysplastic BE in 35 patients. The complete remission rate of BE was comparable in both groups (75% vs 63%; p = 0.49). Subsequently, Sampliner et al46 documented successful removal of BE 45 of 58 patients in a multicenter study.

Argon Plasma Coagulation It is considered as a standard technique for ablation, especially of short segments of BE. In most studies, APC was used to ablate nondysplastic BE. Complications of

APC are strictures, relatively rarely bleeding and very rarely perforations. Van Laethem et al47 found APC is safe and effective in the management of HGD and in situ adenocarcinoma associated with BE. Complete eradication of high grade dysplasia and in situ adenocarcinoma was achieved after a mean number of 3.3 ± 1.5 APC sessions in eight of 10 patients (80%). Attwood et al48 treated 29 patients with APC with a mean follow-up period of 37 months. Twenty-five patients had elimination of HGD and 22 patients had elimination of BE. APC appears to be more effective than photodynamic therapy (PDT). A total of 68 patients with BE were randomized to APC (n = 34) or PDT (n = 34). In the APC group, 33 of 34 (97%) ablated, compared with 17 of 34 (50%) in the PDT group.49 Madisch et al50 studied 70 patients with histologically proven non-neoplastic BE; complete BE ablation was achieved by APC and 120 mg omeprazole daily. Among them, 66 patients (94.4%) underwent further surveillance endoscopy. In none of the patients, intraepithelial neoplasia nor an esophageal adenocarcinoma was detected.

Radiofrequency Ablation Radiofrequency ablation (RFA) seems to be the method for ablation with the highest rates of Barrett’s eradication, a very low complication rate and an almost absent risk of residual ‘buried glands.51,52 A focal device (HALO90) fits over the tip of the endoscope and can be used for ablation of smaller areas.53 In a dose-response and efficacy study in patients with nondysplastic BE who underwent treatment with the HALO 360 system, 70% of 70 patients had complete ablation of BE after one year of follow-up.53 Two recently published51,52 studies from the Amsterdam group combined ER of visible neoplastic lesions with circumferential and focal RFA of the remaining BE containing HGD in 23 patients. Ablation without prior endoscopic resection was done in 10 patients with flat high-grade intraepithelial neoplasia (HGIN). Complete elimination of neoplasia and Barrett’s metaplasia was possible in all of the 23 included patients; none of the 836 biopsies of the neosquamous mucosa contained subsquamous BE. In a US multicenter registry with 16 centers,54 142 patients with HGD underwent a mean of one ablation session with the HALO 360 system. A complete removal of HGIN was confirmed in 90.2% and of BE in 54.3%.54 It also seems to be the ideal addendum to endoscopic resection for ablation of the remaining nondysplastic Barrett’s epithelium after successful resection of all localizable HGIN and adenocarcinoma.

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Gastroenterology If there is evidence of fibrosis in the wall of the esophagus, an ablation balloon with a diameter smaller than that determined by the measuring balloon is used to prevent esophageal tears. RFA is not recommended for patients with esophageal strictures because inflation of the treatment balloons (typical diameters of 28-31 mm) could cause perforations. During a follow-up period of 30 months, by using a combination of the balloon-based and focal RFA devices, an uncontrolled study has described complete eradication of Barrett’s epithelium in 60 of 61 patients.55 From 19 US centers, a multicenter, randomized, shamcontrolled trial9 investigated the efficacy of RFA in 127 patients with low-grade intraepithelial neoplasia (LGIN) (n = 63) and HGIN (n = 64). Patients were randomized (2:1) to RFA or sham treatment. The 1-year interim analysis was able to show that 74% of patients randomized to RFA achieved complete clearance of Barrett’s metaplasia compared with 0% in the sham arm. RFA successfully removed HGIN in 83% of patients (10 of 12) and LGIN in 100% (23 of 23). In the sham group, 0% of patients had clearance of HGIN and 36% of LGIN.

Cryotherapy The latest technique of ablation therapy applied to BE with the least experience in human beings is cryotherapy. It works by freezing the mucosa to induce cell death. Two systems have been used including one that sprays liquid nitrogen through an open-tip catheter56 while the other forces a cryogenic refrigerant (carbon dioxide) through a catheter that also provides venting.57 There are two different devices for cryotherapy in the gastrointestinal tract. Raju et al58 have reported that esophageal cryotherapy could result in a dose-dependent injury to the esophagus. In a single-center, retrospective study, among 36 patients, 33 patients (92%) achieved a complete response; in the remaining three patients, LGD was diagnosed in one patient and intestinal metaplasia was diagnosed in two patients.59 Nonrandomized and uncontrolled studies show success rates comparable to other ablative modalities for the treatment of BE with HGD, with complete eradication of dysplasia seen in 87-96% and complete eradication of intestinal metaplasia in 57-96% of treated patients. In earlystage esophageal cancer, spray cryotherapy appears to have a unique role, eliminating mucosal cancer in 75% of patients, including those who have failed other modalities.60

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Photodynamic Therapy Photodynamic therapy (PDT) is an established endoscopic technique for ablating BE with HGD or early-stage intraepithelial neoplasia and has been successfully used to treat early neoplasia in BE for more than one decade. The most common clinically significant adverse effect seen in more than 30% of the patients who were treated with PDT developed esophageal strictures,10 which is usually superficial and might be dilated effectively with standard endoscopic accessories, such as endoscope balloon or Savary dilators.61 In BE, are used a variety of different agents, including porfimer sodium and 5-aminolevulinic acid (5-ALA) and used.10,62 In a large multicentric randomized trial utilizing intravenous porfimer sodium, a photosensitizer, 255 patients with HGIN were treated by PDT and proton pump inhibitors (PPIs) or PPI only. Ablation of all HGD was noted in 77% of patients in the PDT arm versus 39% in the control arm. Significantly fewer patients progressed to cancer in the PDT arm than in the PPI arm (13 vs 28%).10 However, complications occurred in 94% of the PDT group. Results were similar after five years of follow-up.62 PDT is a highly effective, safe and minimally invasive first-line treatment for patients with Barrett’s dysplasia and mucosal adenocarcinoma. Wolfsen et al63 used porfimer sodium photodynamic therapy to treat patients with BE and HGD or mucosal carcinoma; 102 patients with Barrett’s HGD (69 patients) or mucosal adenocarcinoma (33 patients) were treated with PDT using porfimer sodium as an alternative to esophagectomy. Overall treatment results found complete ablation of glandular epithelium with one course of PDT in most patients (56%). Prasad et al64 demonstrated in 126 patients that p16 allelic loss predicted decreased response to PDT with an OR of 0.32. Other independent predictors of loss of dysplasia were the length of the Barrett’s segment and the performance of PDT. Porfimer-photodynamic therapy with supplemental Nd:YAG photoablation and continuous treatment with omeprazole reduces the length of Barrett’s mucosa, eliminates HGD, and by comparison with historical data, may reduce the expected frequency of carcinoma. Overholt et al65 performed Porfimer-photodynamic therapy in 103 patients. The Nd:YAG laser was used to photoablate small areas of residual or untreated Barrett’s mucosa. Acid suppression was maintained in

Gastroenterology all patients (omeprazole, 20 mg twice-daily). Among 103 patients, intention-to-treat success rates were 92.9%, 77.5%, and 44.4% for, respectively, LGD, HGD, and early-stage carcinoma groups. In addition, PDT is associated with upto a 36% rate of strictures and causes temporary cutaneous photosensitivity, but, in long-term follow-up, all the strictures responded to endoscopic therapy.10,62 PDT is well-tolerated and highly effective with long-term complete remission rates of more than 94%.66 PDT with porfimer sodium is expensive and associated with a high complication rate. Photosensitivity and stricture formation in upto 30% of patients are important drawbacks of this method.

Endoscopic Mucosal Resection There are two concepts for endoscopic mucosal resection (EMR): lesions can either be removed en bloc or piecemeal. EMR allows for more precise characterization of neoplasia, less interobserver variation among pathologists, more accurate assessments of dysplasia grades and the depths of invasion.67 Endoscopic therapy might be curative for most patients with neoplasms confined to the mucosa. For tumors that involve the submucosa, however, the rate of metastasis to the lymph nodes exceeds 20%.68 Until recently, few studies with large patient numbers or long follow-up were available for EMR. Recently, Pech et al66 published endoscopic treatment of early Barrett’s neoplasia in 349 patients. EMR was performed in 279 patients, PDT in 55 patients and both methods were combined in 13 patients; two patients received APC. It was highly-effective treatment with a remission rate of 96.6%. However, metachronous and recurrent neoplasia was observed in 21.5% of cases during a follow-up of >5 years. Most patients were retreated successfully and long-term complete response was achieved in 84%. In recent study,69 100 consecutive patients were treated with EMR and followed up for a mean of three years with a calculated 5-year survival rate of 98%. Sixtynine percent of the patients had short-segment BE. The recurrent or metachronous cancer rate was 11% with successful re-treatment with EMR. The Amsterdam group70 treated 37 patients with stepwise radical endoscopic concept. Complete eradication of early neoplasia was achieved in all 37 patients treated in a median number of three sessions, and complete removal of all Barrett’s mucosa was achieved in 33 patients (89%). No recurrences had been observed after 11 months. The drawback of EMR with the suck-andcut technique is that only small lesions with a diameter of <20 mm can be resected en bloc with tumor-free lateral margins.

Conclusion BE is a premalignant metaplastic process that typically involves the distal esophagus. Its presence is suspected by endoscopic evaluation of the esophagus, but the diagnosis is confirmed by histologic analysis of endoscopically biopsied tissue. Screening and surveillance for BE remain very controversial topics. Identified guidelines for both screening and surveillance have been proposed, they are variable and not evidence-based. The rapid advance of endoscopic therapeutic techniques in the last decade has made it an acceptable alternative to an esophagectomy in patients with HGD and early esophageal adenocarcinoma (EAC). Patients diagnosed with BE are recommended to undergo endoscopic surveillance of BE every 3–5 years. Endoscopic treatment is carried out effectively and safely if patients fulfill certain low risk criteria for lymph node involvement. New endoscopic therapies have evolved that provide an effective, nonsurgical means of eradicating BE with dysplasia and early EAC. Although there have not been any randomized controlled trials comparing endoscopic therapies with esophagectomy in patients with HGD and early esophageal cancer, limited long-term outcome has been promising and shows a high rate of eradication of dysplasia and intestinal metaplasia with endotherapy. Endoscopic treatments have the additional advantages of being outpatient procedures with shorter recovery times. A combination of different endoscopic treatments may provide the best outcomes. Given that relatively few patients need these treatments each year, offering them at specialized centers will concentrate clinical expertise and be the most cost-effective approach. References 1. American Gastroenterological Association, Spechler SJ, Sharma P, Souza RF, Inadomi JM, Shaheen NJ. American Gastroenterological Association medical position statement on the management of Barrett’s esophagus. Gastroenterology 2011;140(3):1084-91. 2. Wang KK, Sampliner RE; Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines 2008 for the diagnosis, surveillance and therapy of Barrett’s esophagus. Am J Gastroenterol 2008;103(3):788-97. 3. Cook MB, Wild CP, Forman D. A systematic review and meta-analysis of the sex ratio for Barrett’s esophagus, erosive reflux disease, and nonerosive reflux disease. Am J Epidemiol 2005;162(11):1050-61. 4. Avidan B, Sonnenberg A, Schnell TG, Sontag SJ. Hiatal hernia and acid reflux frequency predict presence and

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Gastroenterology length of Barrett’s esophagus. Dig Dis Sci 2002;47(2): 256-64.

esophagus at the index endoscopy. Am J Gastroenterol 1999;94(4):937-43.

5. Ronkainen J, Aro P, Storskrubb T, Johansson SE, Lind T, Bolling-Sternevald E, et al. Prevalence of Barrett’s esophagus in the general population: an endoscopic study. Gastroenterology 2005;129(6):1825-31.

20. Kim SL, Waring JP, Spechler SJ, Sampliner RE, Doos WG, Krol WF, et al. Diagnostic inconsistencies in Barrett’s esophagus. Department of Veterans Affairs Gastroesophageal Reflux Study Group. Gastroenterology 1994;107(4):945-9.

6. Kubo A, Levin TR, Block G, Rumore GJ, Quesenberry CP Jr, Buffler P, et al. Alcohol types and sociodemographic characteristics as risk factors for Barrett’s esophagus. Gastroenterology 2009;136(3):806-15. 7. Spechler SJ. Clinical practice. Barrett’s esophagus. N Engl J Med 2002;346(11):836-42. 8. Shaheen NJ, Richter JE. Barrett’s oesophagus. Lancet 2009;373(9666):850-61. 9. Shaheen NJ, Sharma P, Overholt BF, Wolfsen HC, Sampliner RE, Wang KK, et al. Radiofrequency ablation in Barrett’s esophagus with dysplasia. N Engl J Med 2009;360(22):2277-88. 10. Overholt BF, Lightdale CJ, Wang KK, Canto MI, Burdick S, Haggitt RC, et al; International Photodynamic Group for High-Grade Dysplasia in Barrett’s Esophagus. Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Barrett’s esophagus: international, partially blinded, randomized phase III trial. Gastrointest Endosc 2005;62(4):488-98. 11. Barritt AS 4th, Shaheen NJ. Should patients with Barrett’s oesophagus be kept under surveillance? The case against. Best Pract Res Clin Gastroenterol 2008;22(4):741-50. 12. Fléjou JF. Barrett’s oesophagus: from metaplasia to dysplasia and cancer. Gut 2005;54 Suppl 1:i6-12. 13. Spechler SJ. Columnar-lined esophagus. Definitions. Chest Surg Clin N Am 2002;12(1):1-13, vii. 14. Gopal DV, Lieberman DA, Magaret N, Fennerty MB, Sampliner RE, Garewal HS, et al. Risk factors for dysplasia in patients with Barrett’s esophagus (BE): results from a multicenter consortium. Dig Dis Sci 2003;48(8):1537-41.

21. Curvers WL, Peters FP, Elzer B, Schaap AJ, Baak LC, van Oijen A, et al. Quality of Barrett’s surveillance in The Netherlands: a standardized review of endoscopy and pathology reports. Eur J Gastroenterol Hepatol 2008;20(7):601-7. 22. Abrams JA, Kapel RC, Lindberg GM, Saboorian MH, Genta RM, Neugut AI, et al. Adherence to biopsy guidelines for Barrett’s esophagus surveillance in the community setting in the United States. Clin Gastroenterol Hepatol 2009;7(7):736-42; quiz 710. 23. Streitz JM Jr, Andrews CW Jr, Ellis FH Jr. Endoscopic surveillance of Barrett’s esophagus. Does it help? J Thorac Cardiovasc Surg 1993;105(3):383-7; discussion 387-8. 24. Fountoulakis A, Zafirellis KD, Dolan K, Dexter SP, Martin IG, Sue-Ling HM. Effect of surveillance of Barrett’s oesophagus on the clinical outcome of oesophageal cancer. Br J Surg 2004;91(8):997-1003. 25. Corley DA, Levin TR, Habel LA, Weiss NS, Buffler PA. Surveillance and survival in Barrett’s adenocarcinomas: a population-based study. Gastroenterology 2002;122(3):633-40. 26. Cooper GS, Kou TD, Chak A. Receipt of previous diagnoses and endoscopy and outcome from esophageal adenocarcinoma: a population-based study with temporal trends. Am J Gastroenterol 2009;104(6):1356-62. 27. Kearney DJ, Crump C, Maynard C, Boyko EJ. A case-control study of endoscopy and mortality from adenocarcinoma of the esophagus or gastric cardia in persons with GERD. Gastrointest Endosc 2003;57(7):823-9.

15. Pohler E, Craig AL, Cotton J, Lawrie L, Dillon JF, Ross P, et al. The Barrett’s antigen anterior gradient-2 silences the p53 transcriptional response to DNA damage. Mol Cell Proteomics 2004;3(6):534-47.

28. Sampliner RE; Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines for the diagnosis, surveillance, and therapy of Barrett’s esophagus. Am J Gastroenterol 2002;97(8): 1888-95.

16. Murray E, McKenna EO, Burch LR, Dillon J, LangridgeSmith P, Kolch W, et al. Microarray-formatted clinical biomarker assay development using peptide aptamers to anterior gradient-2. Biochemistry 2007;46(48):13742-51.

29. Inadomi JM, Sampliner R, Lagergren J, Lieberman D, Fendrick AM, Vakil N. Screening and surveillance for Barrett esophagus in high-risk groups: a cost-utility analysis. Ann Intern Med 2003;138(3):176-86.

17. Eloubeidi MA, Provenzale D. Clinical and demographic predictors of Barrett’s esophagus among patients with gastroesophageal reflux disease: a multivariable analysis in veterans. J Clin Gastroenterol 2001;33(4):306-9.

30. Mandal A, Playford RJ, Wicks AC. Current practice in surveillance strategy for patients with Barrett’s oesophagus in the UK. Aliment Pharmacol Ther 2003;17(10):1319-24.

18. Conio M, Filiberti R, Blanchi S, Ferraris R, Marchi S, Ravelli P, et al; Gruppo Operativo per lo Studio delle Precancerosi Esofagee (GOSPE). Risk factors for Barrett’s esophagus: a case-control study. Int J Cancer 2002;97(2):225-9. 19. Eloubeidi MA, Provenzale D. Does this patient have Barrett’s esophagus? The utility of predicting Barrett’s

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31. Society for Surgery of the Alimentary Tract. SSAT patient care guidelines. Management of Barrett’s esophagus. J Gastrointest Surg 2007;11(9):1213-5. 32. Montgomery E, Bronner MP, Goldblum JR, Greenson JK, Haber MM, Hart J, et al. Reproducibility of the diagnosis of dysplasia in Barrett esophagus: a reaffirmation. Hum Pathol 2001;32(4):368-78.

Gastroenterology 33. Sharma P, Falk GW, Weston AP, Reker D, Johnston M, Sampliner RE. Dysplasia and cancer in a large multicenter cohort of patients with Barrett’s esophagus. Clin Gastroenterol Hepatol 2006;4(5):566-72. 34. Wani S, Mathur S, Sharma P. How to manage a Barrett’s esophagus patient with low-grade dysplasia. Clin Gastroenterol Hepatol 2009;7(1):27-32. 35. Rastogi A, Puli S, El-Serag HB, Bansal A, Wani S, Sharma P. Incidence of esophageal adenocarcinoma in patients with Barrett’s esophagus and high-grade dysplasia: a meta-analysis. Gastrointest Endosc 2008;67(3):394-8. 36. Jobe BA, Hunter JG, Chang EY, Kim CY, Eisen GM, Robinson JD, et al. Office-based unsedated smallcaliber endoscopy is equivalent to conventional sedated endoscopy in screening and surveillance for Barrett’s esophagus: a randomized and blinded comparison. Am J Gastroenterol 2006;101(12):2693-703. 37. Lin OS, Schembre DB, Mergener K, Spaulding W, Lomah N, Ayub K, et al. Blinded comparison of esophageal capsule endoscopy versus conventional endoscopy for a diagnosis of Barrett’s esophagus in patients with chronic gastroesophageal reflux. Gastrointest Endosc 2007;65(4):577-83. 38. Galmiche JP, Sacher-Huvelin S, Coron E, Cholet F, Soussan EB, Sébille V, et al. Screening for esophagitis and Barrett’s esophagus with wireless esophageal capsule endoscopy: a multicenter prospective trial in patients with reflux symptoms. Am J Gastroenterol 2008;103(3):538-45. 39. Wolfsen HC, Crook JE, Krishna M, Achem SR, Devault KR, Bouras EP, et al. Prospective, controlled tandem endoscopy study of narrow band imaging for dysplasia detection in Barrett’s esophagus. Gastroenterology 2008;135(1):24-31. 40. Kiesslich R, Gossner L, Goetz M, Dahlmann A, Vieth M, Stolte M, et al. In vivo histology of Barrett’s esophagus and associated neoplasia by confocal laser endomicroscopy. Clin Gastroenterol Hepatol 2006;4(8):979-87. 41. Soni A, Sampliner RE, Sonnenberg A. Screening for highgrade dysplasia in gastroesophageal reflux disease: is it cost-effective? Am J Gastroenterol 2000;95(8):2086-93. 42. Inadomi JM, Sampliner R, Lagergren J, Lieberman D, Fendrick AM, Vakil N. Screening and surveillance for Barrett esophagus in high-risk groups: a cost-utility analysis. Ann Intern Med 2003;138(3):176-86. 43. Isenberg G, Sivak MV Jr, Chak A, Wong RC, Willis JE, Wolf B, et al. Accuracy of endoscopic optical coherence tomography in the detection of dysplasia in Barrett’s esophagus: a prospective, double-blinded study. Gastrointest Endosc 2005;62(6):825-31. 44. Allison H, Banchs MA, Bonis PA, Guelrud M. Long-term remission of nondysplastic Barrett’s esophagus after multipolar electrocoagulation ablation: report of 139 patients with 10 years of follow-up. Gastrointest Endosc 2011;73(4):651-8.

45. Sharma P, Wani S, Weston AP, Bansal A, Hall M, Mathur S, et al. A randomised controlled trial of ablation of Barrett’s oesophagus with multipolar electrocoagulation versus argon plasma coagulation in combination with acid suppression: long term results. Gut 2006;55(9):1233-9. 46. Sampliner RE, Faigel D, Fennerty MB, Lieberman D, Ippoliti A, Lewin K, et al. Effective and safe endoscopic reversal of nondysplastic Barrett’s esophagus with thermal electrocoagulation combined with high-dose acid inhibition: a multicenter study. Gastrointest Endosc 2001;53(6):554-8. 47. Van Laethem JL, Jagodzinski R, Peny MO, Cremer M, Devière J. Argon plasma coagulation in the treatment of Barrett’s high-grade dysplasia and in situ adenocarcinoma. Endoscopy 2001;33(3):257-61. 48. Attwood SE, Lewis CJ, Caplin S, Hemming K, Armstrong G. Argon beam plasma coagulation as therapy for highgrade dysplasia in Barrett’s esophagus. Clin Gastroenterol Hepatol 2003;1(4):258-63. 49. Kelty CJ, Ackroyd R, Brown NJ, Stephenson TJ, Stoddard CJ, Reed MW. Endoscopic ablation of Barrett’s oesophagus: a randomized-controlled trial of photodynamic therapy vs. argon plasma coagulation. Aliment Pharmacol Ther 2004;20(11-12):1289-96. 50. Madisch A, Miehlke S, Bayerdorffer E, Wiedemann B, Antos D, Sievert A, et al. Long-term follow-up after complete ablation of Barrett’s esophagus with argon plasma coagulation. World J Gastroenterol 2005;11(8):1182-6. 51. Gondrie JJ, Pouw RE, Sondermeijer CM, Peters FP, Curvers WL, Rosmolen WD, et al. Effective treatment of early Barrett’s neoplasia with stepwise circumferential and focal ablation using the HALO system. Endoscopy 2008;40(5):370-9. 52. Gondrie JJ, Pouw RE, Sondermeijer CM, Peters FP, Curvers WL, Rosmolen WD, et al. Stepwise circumferential and focal ablation of Barrett’s esophagus with high-grade dysplasia: results of the first prospective series of 11 patients. Endoscopy 2008;40(5):359-69. 53. Sharma VK, Wang KK, Overholt BF, Lightdale CJ, Fennerty MB, Dean PJ, et al. Balloon-based, circumferential, endoscopic radiofrequency ablation of Barrett’s esophagus: 1-year follow-up of 100 patients. Gastrointest Endosc 2007;65(2):185-95. 54. Ganz RA, Overholt BF, Sharma VK, Fleischer DE, Shaheen NJ, Lightdale CJ, et al; U.S. Multicenter Registry. Circumferential ablation of Barrett’s esophagus that contains high-grade dysplasia: a U.S. Multicenter Registry. Gastrointest Endosc 2008;68(1):35-40. 55. Fleischer DE, Overholt BF, Sharma VK, Reymunde A, Kimmey MB, Chuttani R, et al. Endoscopic ablation of Barrett’s esophagus: a multicenter study with 2.5-year follow-up. Gastrointest Endosc 2008;68(5):867-76. 56. Johnston MH, Horwhat JD, Dubois A, Schoenfeld PS. Endoscopic cryotherapy in the swine esophagus: a follow up study [Abstract]. Gastrointest Endosc 1999;49:AB126.

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Gastroenterology 57. Pasricha PJ, Hill S, Wadwa KS, Gislason GT, Okolo PI 3rd, Magee CA, et al. Endoscopic cryotherapy: experimental results and first clinical use. Gastrointest Endosc 1999;49(5):627-31. 58. Raju GS, Ahmed I, Xiao SY, Brining D, Bhutani MS, Pasricha PJ. Graded esophageal mucosal ablation with cryotherapy, and the protective effects of submucosal saline. Endoscopy 2005;37(6):523-6. 59. Halsey KD, Chang JW, Waldt A, Greenwald BD. Recurrent disease following endoscopic ablation of Barrett’s highgrade dysplasia with spray cryotherapy. Endoscopy 2011;43(10):844-8. 60. Greenwald BD, Dumot JA. Cryotherapy for Barrett’s esophagus and esophageal cancer. Curr Opin Gastroenterol 2011;27(4):363-7. 61. Cheon YK. Metal stenting to resolve post-photodynamic therapy stricture in early esophageal cancer. World J Gastroenterol 2011;17(10):1379-82. 62. Overholt BF, Wang KK, Burdick JS, Lightdale CJ, Kimmey M, Nava HR, et al; International Photodynamic Group for High-Grade Dysplasia in Barrett’s Esophagus. Five-year efficacy and safety of photodynamic therapy with Photofrin in Barrett’s high-grade dysplasia. Gastrointest Endosc 2007;66(3):460-8. 63. Wolfsen HC, Hemminger LL, Wallace MB, Devault KR. Clinical experience of patients undergoing photodynamic therapy for Barrett’s dysplasia or cancer. Aliment Pharmacol Ther 2004;20(10):1125-31. 64. Prasad GA, Wang KK, Halling KC, Buttar NS, Wongkeesong LM, Zinsmeister AR, et al. Utility of biomarkers in prediction of response to ablative therapy

in Barrett’s esophagus. Gastroenterology 2008;135(2): 370-9. 65. Overholt BF, Panjehpour M, Halberg DL. Photodynamic therapy for Barrett’s esophagus with dysplasia and/or early stage carcinoma: long-term results. Gastrointest Endosc 2003;58(2):183-8. 66. Pech O, Behrens A, May A, Nachbar L, Gossner L, Rabenstein T, et al. Long-term results and risk factor analysis for recurrence after curative endoscopic therapy in 349 patients with high-grade intraepithelial neoplasia and mucosal adenocarcinoma in Barrett’s oesophagus. Gut 2008;57(9):1200-6. 67. Peters FP, Brakenhoff KP, Curvers WL, Rosmolen WD, Fockens P, ten Kate FJ, et al. Histologic evaluation of resection specimens obtained at 293 endoscopic resections in Barrett’s esophagus. Gastrointest Endosc 2008;67(4): 604-9. 68. Prasad GA, Buttar NS, Wongkeesong LM, Lewis JT, Sanderson SO, Lutzke LS, et al. Significance of neoplastic involvement of margins obtained by endoscopic mucosal resection in Barrett’s esophagus. Am J Gastroenterol 2007;102(11):2380-6. 69. Ell C, May A, Pech O, Gossner L, Guenter E, Behrens A, et al. Curative endoscopic resection of early esophageal adenocarcinomas (Barrett’s cancer). Gastrointest Endosc 2007;65(1):3-10. 70. Peters FP, Kara MA, Rosmolen WD, ten Kate FJ, Krishnadath KK, van Lanschot JJ, et al. Stepwise radical endoscopic resection is effective for complete removal of Barrett’s esophagus with early neoplasia: a prospective study. Am J Gastroenterol 2006;101(7):1449-57.

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Fecal Microbial Transplantation for Ulcerative Colitis Fecal microbial transplantation (FMT) via enema is shown to be effective, tolerable, and feasible for treating children with ulcerative colitis (UC), according to findings from a phase 1 pilot study published online March 29 and in the June issue of the Journal of Pediatric Gastroenterology and Nutrition. It involves infusion of human stool from a healthy adult donor into the patient's intestine and has been proposed as an option for recurrent (Clostridium) difficile infection and possibly for ulcerative colitis as per Sachin Kunde, MD, MPH, from Spectrum Health Medical Group, Helen DeVos Children's Hospital in Grand Rapids, Michigan. The procedure may restore 'abnormal' bacteria to 'normal' in patients with (UC). Ten children, aged 7 to 21 years, who had mild to moderate UC, received freshly prepared fecal enemas daily for five days. The investigators collected data on tolerability, adverse events, and disease activity during FMT and weekly for 4 weeks thereafter. At baseline, pediatric UC activity index ranged from 15 to 65. The investigators considered a reduction in PUCAI by more than 15 to be clinical response, and PUCAI lower than 10 to be clinical remission. There were no serious adverse events. Self-limiting adverse events were mild cramping, fullness, flatulence, bloating, diarrhea, blood in the stool, and moderate fever. Although 1 child could not retain fecal enemas, average tolerated enema volume in the other 9 children was 165 ml/day. Clinical response within 1 week occurred in 7 (78%) of the 9 children, including 3 (33%) who had clinical remission and 6 (67%) who maintained clinical response at 1 month. Compared with baseline, median PUCAI significantly improved after FMT. (Source: Medscape)

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Infectious Disease

Study of Antioxidant Enzymes, MDA and Lipid Profile in Cerebral Malaria A Tyagi*, R Tyagi*, R Vekariya**, A Ahujaâ&#x20AC;

Abstract Cerebral malaria (CM) is the most important complication of falciparum malaria. However, its pathophysiology is not understood. Malaria infection is accompanied by increased production of reactive oxygen species (ROS) and the malaria parasites are sensitive to oxidative damage. So, we conducted a case-control study to estimate antioxidant activity, lipid peroxidation in 36 patients with CM. In present study, catalase (CAT), reduced glutathione (GSH) and lipid peroxidation product malondialdehyde (MDA) were increased significantly and superoxide dismutase (SOD) was decreased significantly in CM patients at the time of admission with respect to control group. After treatment, SOD activity was increased and MDA level was decreased; rest of the parameters did not show any significant change. So, the antioxidant enzyme has a prognostic role in CM.

Keywords: Cerebral malaria, catalase, reduced glutathione, superoxide dismutase, malondialdehyde

erebral malaria (CM) collectively involves the clinical manifestations of Plasmodium falciparum malaria that induce changes in mental status and coma. It is an acute, widespread disease of brain, which is accompanied by fever. The mortality ratio is between 25-50%. If a person is not treated, CM is fatal in 24-72 hours. The histopathological hallmark of this encephalopathy is the sequestration of cerebral capillaries and venules with parasitized red blood cells (PRBCs) and non-PRBCs (NPRBCs). Ring-like lesions in the brain are major characteristics. The pathophysiology of CM is not completely understood. Malaria infection is accompanied by increased production of reactive oxygen species (ROS) and the malaria parasites are sensitive to oxidative damage.

Aim The present study was planned to evaluate oxidative stress inpatients of CM and compare with that in control group.

*Associate Professor Dept. of Biochemistry **PG Student, Dept. of Medicine CU Shah Medical College, Surendranagar, Gujarat â&#x20AC; Pathologist, CU Shah Diagnostic Center, CJ Hospital, Surendranagar, Gujarat Address for correspondence Dr Amit Tyagi Associate Professor, Dept. of Biochemistry, CU Shah Medical College Dudhraj Road, Surendranagar, Gujarat - 363 001 E-mail: ami_tyagi2001@yahoo.com

MATERIAL AND METHODS Thirty-six patients of CM diagnosed in accordance to the guideline from medicine ward were selected in study group. Twenty-five age- and sex-matched healthy subject were selected in control group. Blood samples were collected in plain and ethylenediamine-tetraacetic (EDTA) bulb at the time of admission and before one day of the discharge of the patients. Erythrocytic reduced glutathione (GSH) was measured by Beutler method, catalase (CAT) was measured by Sinha method, superoxide dismutase (SOD) was measured by Fridorich method and plasma malondialdehyde (MDA) was estimated by Buege method. Lipid profile i.e. total cholesterol, triglyceride and high-density liporotein (HDL) cholesterol were tested by Accurex enzymatic kit method. DISCUSSION It is known that malarial infection is accompanied by increased production of ROS and the malarial parasites are sensitive to oxidative damage. The univalent reduction of oxygen results in a series of cytotoxic oxygen species such as superoxide anions (O2-), hydrogen peroxide (H2O2) and hydroxyl radicals (OH-). These highly reactive species can cause a wide-spectrum of cell damage including lipid peroxidation, inactivation of enzymes, alteration of

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Infectious Disease Table 1. Comparative Levels of Erythrocytic GSH, CAT, SOD, Plasma MDA and Serum Lipid Profile in Control, CM Patients (At Admission) and after Treatment Parameters

Control (Mean ± SD)

CM patients (At admission) (Mean ± SD)

Erythrocytic GSH (gm/Hb%)

8.31 ± 2.18

31.6 ± 18.3

<0.001

31.6 ± 22

>0.05

Erythrocytic CAT (µmol/sec)

6.99 ± 2.45

16 ± 7.3

<0.001

19.3 ± 7.8

>0.05

Erythrocytic SOD (EU)

1.43 ± 0.16

1.2 ± 0.50

<0.05

1.54 ± 0.31

<0.01

Plasma MDA (nM/l)

6.44 ± 5.8

11 ± 5.4

<0.001

7.23 ± 2.6

<0.001

Serum total cholesterol (mg/dl)

180 ± 41

175 ± 31

>0.05

173 ± 28

>0.05

Serum triglyceride (mg/dl)

105 ± 42

193 ± 88

<0.001

177 ± 65

>0.05

Serum HDL cholesterol (mg/dl)

44 ± 12

43 ± 12

>0.05

47 ± 10.4

>0.05

Serum VLDL cholesterol (mg/dl)

21 ± 8.3

39 ± 18

<0.001

35.5 ± 13

>0.05

Serum LDL cholesterol (mg/dl)

113 ± 43

92 ± 42

>0.05

92 ± 32

>0.05

P value (Control CM patients P value vs At admission) (After treatment) (At admission vs (Mean ± SD) After treatment)

2 1.8

1 0.8

20 2.18

31.6

CM patients (at admission)

0 Controls

16 7.8

2.45

19.3

10 8 6 4

5.8

6.44

2.6 11 7.23

6.99 Controls

5.4

7.3 nM/L

umol/sec.

CM patients CM patients (At admission) (After treatment)

Figure 2. Comparative levels of erythrocytic CAT in controls, CM patients (at admission) and after treatment.

intracellular oxidation-reduction state and damage to DNA. Mammalian cells posses enzymatic antioxidant defenses to cope with oxygen free radicals e.g.: SOD, CAT and GSH peroxidase. In the present study, oxidative stress and antioxidant defense system were altered in CM. The levels of

824

CM patients (After treatment)

CM patients (At admission)

Figure 3. Comparative levels of erythrocytic SOD in controls, CM patients (at admission) and after treatment.

1.2

0.4

CM patients (After treatment)

Figure 1. Comparative levels of erythrocytic GSH in controls, CM patients (At admission) and after treatment.

1.54

1.43

0.6 0.2

8.31 Controls

0.5

1.2

0.16

1.4

18.3

g/Hb%

0.31

1.6

Indian Journal of Clinical Practice, Vol. 23, No. 12, May 2013

Controls

CM patients CM patients (At admission) (After treatment)

Figure 4. Comparative levels of plasma MDA in controls, CM patients (at admission) and after treatment.

reduced GSH, CAT, MDA, triglycerides and VLDL cholesterol were increased significantly (p < 0.001) at the time of admission in CM patients compared to that of control (Table 1, Figs. 1, 2, 4 and 5). While after the treatment, SOD levels were increased (Table 1 and Fig. 3) and MDA level was decreased (Table 1 and Fig. 4)

Infectious Disease 300

Triglycerides

250

T. cholesterol

umol/sec.

200 LDL cholesterol

150 100 HDL cholesterol

VLDL cholesterol

50 0

Controls

CM patients CM patients (After (At admission) treatment)

Controls

CM patients CM patients (After (At admission) treatment)

Controls

CM patients CM patients (After (At admission) treatment)

Controls

CM patients CM patients Controls (After (At admission) treatment)

CM patients CM patients (After (At admission) treatment)

Figure 5. Comparative levels of serum lipid profile in control, CM patients (at admission) and after treatment.

falling almost in the range observed in control. Rest of the parameters did not show any significant change (Table 1 and Figs. 1, 2 & 5). Conclusion The study suggests that monitoring of SOD and MDA parameters can be useful in prognosis of CM patients. Suggested reading

antioxidant defense indices in humans. Drug Chem Toxicol 2003;26(1):59-71. 3. Beutler E, Duron O, Kelly BM. Improved method for the determination of blood glutathione. J Lab Clin Med 1963;61:882-8. 4. Sinha AK. Colorimetric assay of catalase. Anal Biochem 1972;47(2):389-94. 5. Fridovich I. Superoxide dismutases. Adv Enzymol Relat Areas Mol Biol 1974;41(0):35-97. 6. Buege et al. Methods of Enzymology. 1975.

1. Robert S Desowitz. The history of malaria. 2. Farombi EO, Shyntum YY, Emerole GO. Influence of chloroquine treatment and Plasmodium falciparum malaria infection on some enzymatic and non-enzymatic

7. Ceballos-Picot I, Trivier JM, Nicole A, Sinet PM, Thevenin M. Age-correlated modifications of copper-zinc superoxide dismutase and glutathione-related enzyme activities in human erythrocytes. Clin Chem 1992;38(1): 66-70.

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New Guidelines: Screen all Patients Aged 15-65 Years for HIV The US Preventive Services Task Force (USPSTF) recommends screening all adults and adolescents aged 15-65 years for HIV, according to updated guidelines published online April 29 in the Annals of Internal Medicine. The new recommendation also applies to all pregnant women who have not yet been screened, including those in labor. (Source: Medscape)

New Sex 'Superbug' may be More Infectious than AIDS Doctors are warning of a new sexually-transmitted superbug, which they fear could ultimately prove to be even more deadly than AIDS. The antibiotic-resistant strain of gonorrhea - now considered a superbug - was discovered in Japan two years ago. Experts have warned that the bacteria's effects could match those of AIDS. (Source: TOI, May 7, 2013)

Chickens Pegged as Source of H7N9 Flu Evidence from a single patient infected with the novel avian influenza virus H7N9 points to transmission from live poultry, Chinese researchers reported. The finding suggests that live poultry could be the source of the H7N9 outbreak, which has sickened 108 people in eastern China and killed 22 according to the latest official update from the World Health Organization. Investigations into the source are ongoing. (Source: Medpage Today)

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825

Internal Medicine

Prevalence Study of Vitamin D Deficiency and to Evaluate the Efficacy of Vitamin D3 Granules 60,000 IU Supplementation in Vitamin D Deficient Apparently Healthy Adults Pravina Shah*, Sudhindra Kulkarni**, S Narayani†, Dhara Sureka‡, Supriya Dutta¶, Ankita S Vipat#, Qayum Mukaddam§, Kamlesh Patel§, Sachin Suryawanshi§, Manoj Naik£, Manoj Prabhu£

Abstract Objective: The objective of this study was to assess the prevalence of vitamin D deficiency in apparently healthy urban adults and to evaluate the efficacy of vitamin D3 granules 60,000 IU supplementation in increasing serum 25 hydroxyvitamin D [25(OH)D] levels. Material and methods: Healthy adults in an urban hospital were screened for 25(OH)D (radioimmunoassay method). Those found to be deficient or insufficient in vitamin D (defined as 25(OH)D <30 ng/ml) were supplemented with oral cholecalciferol granules 60,000 IU/week for eight weeks. Serum 25(OH)D level was estimated at the end of 60 days. Results: A total of 510 subjects (age 19-66 years) were enrolled for the study. Baseline data was available for 474 subjects and 178 subjects consumed a total of eight sachets as per the study protocol. Of these 178 subjects, 94.94% subjects were found to be vitamin D deficient (<20 ng/ml) and the mean plasma vitamin D3 25(OH)D level was 9.36 ng/ml (±5.19) at baseline. At the end of the study, the mean 25(OH)D plasma level was noted to be 29.28 ng/ml (±13.57). The mean change from baseline was 19.92 ng/ml (±13.25). Among these 178 participants only 5.06% had 25(OH)D >20 ng/ml at baseline, which increased to 78.09% at the end of the study following vitamin D3 supplementation for eight weeks. Conclusion: This study showed that vitamin D deficiency is highly prevalent in the urban healthy adult population. Eight weeks of vitamin D3 60,000 IU/week oral granules supplementation increased serum 25(OH)D to optimal levels.

Keywords: Vitamin D deficiency, adults, 25(OH)D

itamin D has been traditionally known as the antiricketic factor or the sunshine vitamin. It is considered unique due to its ability to be synthesized in the body and functioning as a hormone. Additionally, it plays a crucial role in calcium homeostasis and bone mineral metabolism. Vitamin D endocrine system is also known to support a wide range of fundamental biological

*Consultant Neurologist **Consultant Endocrinologist †Facility Director ‡Senior Resident, Dept. of Neurology ¶Head, Dept. of Lab Medicine #Clinical Research Co-ordinator Fortis Hospitals Ltd., Mulund, Mumbai §Medical Services Division £Clinical Research Division Abbott Healthcare Pvt. Ltd., Mumbai Address for correspondence Dr Sachin Suryawanshi Medical Advisor, Abbott Healthcare Pvt. Ltd., D-Mart Building, Goregaon-Mulund Road Mulund (W), Mumbai - 400 080 E-mail: sachin.suryawanshi@abbott.in

functions in cell differentiation, inhibition of cell growth as well as innate and adaptive immunity.1-3 In adults, chronic vitamin D deficiency leads to osteoporosis, osteomalacia, muscle weakness and increased risk of falls and fractures. Inadequate vitamin D intake and low blood levels of vitamin D metabolites are related to increased incidence of several autoimmune diseases involving the T helper type 1 lymphocyte, including multiple sclerosis, rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus and psoriasis. Lower levels of vitamin D, adjusted for body mass index, are also associated with increased risk of hypertension, myocardial infarction and may lead to death as a result of cardiovascular disease.2 The active metabolite of vitamin D, 1,25-dihydroxyvitamin D [1,25(OH)2D], acts in a wide range of tissues. The vitamin D receptors (VDRs) are present in many cells, including those of the liver, pancreas, brain, lung, breast, skin, muscle and adipose tissue.4 Accumulating research suggests that low serum 25-hydroxyvitamin D3 [25(OH)D]

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Internal Medicine concentrations may be inversely associated with type 2 diabetes, metabolic syndrome, insulin resistance and cardiovascular disease.5 Vitamin D deficiency does indeed constitute an epidemic in many populations across the world and has been reported in healthy population. In India also, more than 90% of apparently healthy Indians have subnormal 25(OH)D levels. Low dietary vitamin D intake and poor exposure to sunlight are common causes of vitamin D deficiency in the general population.12 Sunlight is known to be the primary source of vitamin D and its production in the skin depends on exposure to sunshine, latitude, skin-covering clothes, the use of sunscreen lotions and skin pigmentation in healthy individuals. The vitamin D status depends on the production of vitamin D3 and vitamin D intake through the diet or vitamin D supplements. Usually, upto 90% of vitamin D in the body comes from the production in the skin under the influence of ultraviolet radiation. The preferred and most commonly used parameter for assessment of vitamin D status is serum 25(OH)D concentration. 25(OH)D is the major circulating metabolite of vitamin D and reflects the vitamin D inputs from cutaneous synthesis and dietary intake.5 Usually, serum 25(OH)D is lower at higher latitudes and with darker skin types. Several studies have shown a high prevalence (50-97%) of vitamin D deficiency in tropical and subtropical regions of India and other South Asian countries, despite abundant sunlight.5-7 In India and other parts of world, vitamin D deficiency has been documented across all age groups and both genders. Aim To evaluate the efficacy of vitamin D3 granules 60,000 IU supplementation in vitamin D deficient apparently healthy adults. Material and Methods This open label, single center, prospective prevalence study was conducted at Fortis Hospital, Mulund, Mumbai. The recent Endocrine Society Clinical Practice Guideline on evaluation, treatment and prevention of vitamin D deficiency (published July 2011) was considered for classification of vitamin D deficiency. These guidelines define vitamin D deficiency as 25(OH)D level below 20 ng/ml (50 nmol/l), vitamin D insufficiency as 25(OH)D level at 21-29 ng/ml and sufficiency, if the 25(OH)D level is above 30 ng/ml.8

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An independent Ethical Committee approval was taken and written informed consent from all the participants was obtained.

Study Population The study was planned to include 500 apparently healthy staff members from Fortis Hospital, Mulund, Mumbai. Subjects were enrolled in the study according to the inclusion and exclusion criteria mentioned below. Inclusion Criteria ÂÂ

>18 years of age, upper limit at the discretion of investigator.

ÂÂ

Subjects with 25(OH)D levels <30 ng/ml.

ÂÂ

Ability to understand and the willingness to sign and date a written informed consent at the screening visit before performing any protocolspecific procedures.

Exclusion Criteria ÂÂ

Age <18 years.

ÂÂ

Children, pregnant and lactating mothers.

ÂÂ

Any form of acute illness or terminal illness.

ÂÂ

Uncontrolled diabetes.

ÂÂ

Any form of endocrine disorder, which could alter the plasma levels of vitamin D.

ÂÂ

Those receiving any form of therapy in the preceding one week, which would affect the plasma levels of vitamin D like vitamin D preparations, calcium, corticosteroids, etc.

hypertension

uncontrolled

Study Procedures Staff members of Fortis Hospital, Mulund, Mumbai were screened for vitamin D deficiency by Super Religare Laboratories. The serum 25(OH)D estimation was done using radioimmunoassay (RIA) method. Subjects who had 25(OH)D levels <30 ng/ml were enrolled in the study and were supplemented with vitamin D3 60,000 IU/week for eight weeks as rapid restoration phase. Subjects were instructed to consume the whole sachet with water as per the recommended schedule. Serum vitamin D (25(OH)D) estimation was repeated at follow-up after eight weeks. The study schedule is depicted in Figure 1. The primary endpoint of this study was to assess the prevalence of vitamin D deficiency in urban healthy

Internal Medicine

Screening for serum 25(OH)D

Subjects with 25(OH)D levels <30 ng/ ml enrolled and supplemented with oral cholecalciferol 60,000 IU granules

Follow-up estimation of serum 25(OH)D at 60 days Figure 1. Study methodology.

adult population and the secondary endpoint was to evaluate the efficacy of oral cholecalciferol 60,000 IU granules in increasing 25(OH)D levels from baseline to that at 60 days. Adverse event (AEs) were monitored during the study for safety assessment

Statistical Analysis The statistical analysis was performed in subjects for whom the baseline and follow-up vitamin D levels were available. The measurement data were expressed as means with one standard deviation (SD). The 95% confidence intervals (CI) were computed for differences between the data wherever applicable. Discrete data were expressed as numbers (counts) with percentages (proportions). Vitamin D3 status (ranking data) was compared between baseline and the follow-up period was analyzed for differences using Wilcoxon sign rank test. Vitamin D3 levels and change from baseline in vitamin D3 levels were analyzed for differences in different subgroups gender, age groups using one way ANOVA. Correlation (Pearson’s) was done between changes in plasma vitamin D3 and the number of sachets used. All testing was performed using 2-sided tests at alpha 0.05. Results A total of 510 subjects were enrolled as per the inclusion and exclusion criteria in this single center study. The baseline data of plasma vitamin D was available for 474 subjects while complete baseline and follow-up data were available for 237 subjects. In this article, we present and discuss the data for 178 subjects who consumed all eight sachets of the study drug and completed the study. In spite of the strict follow-up, the number of subjects completing the study was low, probably due to their busy schedule and thereby

inability to follow the procedures and make it for second blood collection or it may be ignorance about vitamin D deficient status and its importance. Table 1 shows the demographic characters of the population for analysis. The number of female subjects was twice the number of male subjects. The mean age was 32.25 years (±7.5). Of these, 46.63% subjects were ≤30 years, 38.76% were in the age group of 31-40 years and only 14.61% were >40 years of age. Vitamin D3 status at baseline is shown in Table 2. The mean plasma vitamin D3 was 9.36 ng/ml (±5.19) and the range was 2.9-28.73 ng/ml. It was observed that most of the subjects (94.94%) were vitamin D deficient and 5.06% were vitamin D insufficient. The change in vitamin D3 plasma levels at followup was evaluated for 178 subjects (Table 3). The follow-up vitamin D3 plasma levels were noted to be 29.28 ng/ml (±13.57) in the range of 3.93-105.72 ng/ml (Fig. 2). The mean change was 19.92 ng/ml (±13.25). There was a >3-fold increase in the 25(OH)D levels with this vitamin D granule formulation. At baseline, out of 178 subjects 5.06% had plasma 25(OH)D level >20 ng/ml (criteria for deficiency), which increased to 78.09% at the end of the study (Fig. 3). The mean changes were also observed according to age group and gender. The subjects in age group of 30-40 years showed mean change from baseline 24.25 ng/ml ± 16.04 followed by those >40 years (18.09 ng/ml ± 7.26) and then ≤30 years (16.89 ng/ml ± 11.11). Table 1. Demographic Characters Gender (n = 178)

No.

Male

32.58

Female Age (years)

120

67.42

Mean

Min.

Max.

32.25

7.50

19.00

62.00

Table 2. Vitamin D3 25(OH)D Status at Baseline (n = 178) Plasma 25(OH)D (ng/ml) Range

Mean

9.36

5.19

2.90-28.73

Plasma vitamin D3 status

No.

Deficiency (<20 ng/ml)

169

94.94

Insufficiency (20-30 ng/ml)

5.06

Sufficiency (>30-40 ng/ml)

0.00

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Internal Medicine Table 3. Change in Vitamin D3 25(OH)D Plasma Levels (n = 178) 25 (OH)D

‘N’

Mean

95% CI

Baseline (ng/ml)

178

9.36

5.19

10.28

11.95

Follow-up (ng/ml)

178

29.28

13.57

25.35

29.13

Change from baseline (ng/ml)

178

19.92

13.25

17.96

21.88

≤30 years

16.89

11.11

14.47

19.32

30-40 years

24.25

16.04

20.40

28.11

>40 years

18.09

7.26

15.16

21.02

Male

20.90

10.66

18.10

23.71

Female

120

19.45

14.36

16.85

22.04

Age groups*

Gender**

*p = 0.002, F = 6.475 (One way ANOVA)

25(OH)D, ng/ml

**p = 0.494, F = 0.470 (One way ANOVA)

Baseline

At the end of study

29.3

No AEs were reported during the study period.

Discussion

15 10

9.36

5 0

Baseline

At the end of study

% of subjects >20 ng/ml

Figure 2. Change in 25(OH)D levels at the end of eight weeks with 60,000 IU vitamin D (n = 178).

78.09

Baseline

At the end of study

60 50 40 30 20 10 0

5.06 Baseline

At the end of study

Figure 3. Subjects reaching 25(OH)D level >20 ng/ml at the end of eight weeks.

830

The change from baseline was noted to be 20.9 ng/ml ± 10.66 in male subjects and 19.45 ng/ml ± 14.36 in female subjects.

Indian Journal of Clinical Practice, Vol. 23, No. 12, May 2013

The understanding of various facets of vitamin D3 has come a long way from being regarded as just a vitamin to now being labeled as a hormone or a metabolic modulator. The awareness about vitamin D sufficiency and its importance in optimal health is increasing. The role of vitamin D in calcium absorption and metabolism for bone health is well-established. Furthermore, since the past two decades, the importance of vitamin D in reducing the risk of cancer, multiple sclerosis and type 1 diabetes mellitus is being explored. There have been many reviews and discussions on the role of vitamin D and prevention of disease and maintenance of optimal health in the past decade.9 This has resulted in the recognition of importance of vitamin D deficiency throughout the life cycle in preventing chronic diseases and maintaining health. Many studies have established that vitamin D deficiency is prevalent in Indians despite the sunny climate throughout the year, irrespective of their age group and gender.1,3,4 In North India (27°N), 96% of neonates, 91% of healthy school girls, 78% of healthy hospital staff and 84% of pregnant women were found to have hypovitaminosis D. In South India (13°N), hypovitaminosis D is equally prevalent among different

Internal Medicine population groups. Hypovitaminosis D is equally prevalent among rural and urban subjects, but in some studies, urban subjects are found to be more deficient.10 Marwaha et al3 showed that 91.2% subjects of >50 years of age had vitamin D deficiency and 6.8% subjects were vitamin D insufficient. In the present study, among 178 subjects, 94.94% had vitamin D deficiency and 5.06% had insufficiency, which is similar to other studies in the past. All the subjects having vitamin D deficiency or insufficiency were supplemented with vitamin D3 granules per week for eight weeks. According to the results established by previous studies,3,11,12 the supplementation of vitamin D3 60,000 IU in the present study was justified. In the study by Goswami et al,12 weekly supplementation of vitamin D granules 60,000 IU resulted in correction of vitamin D level to optimal level after eight weeks of administration. However, to maintain the 25(OH)D levels, vitamin D supplementation has to be ongoing after the eight weeks of vitamin D-loading schedule. Marwaha et al3 mentioned that based on the results of studies, a regular supplementation of at least 2,000 IU/day vitamin D is required to maintain normal vitamin D levels. This study (Marwaha et al) also highlighted the inadequacy of a daily vitamin D intake of 200-400 IU in normalizing serum 25(OH)D.3 About 50% of population of this study was taking calcium and vitamin D supplements. However, there was no difference in serum 25(OH)D levels between those who took and those who did not take supplements. Most of these subjects were taking 200-400 IU of vitamin D3, which is insufficient to normalize serum 25(OH)D levels in a vitamin D deficient population. Recent clinical practice guidelines also recommend vitamin D oral supplementation 50,000-70,000 IU/week for eight weeks in vitamin D deficiency to normalize 25(OH)D levels to above 30 ng/ml. The guidelines also recommend maintaining 25(OH)D blood levels with daily 1,500-2,000 IU vitamin D supplementation. In India, the 60,000 IU granule formulation has been available since many years and is commonly prescribed by physicians across the country in vitamin D deficiency patients. Though, the desired treatment compliance was not observed in this study because of different reasons mentioned earlier, it has put forth certain findings. It showed that regular supplementation of vitamin D3

granules over eight weeks has resulted in positive change to normalize plasma vitamin D3 levels in this population. The study also showed that the lack of awareness was highly prevalent among the consultants as well. The change in plasma vitamin D3 levels of male and female subjects participating in this study was comparable. While analyzing the results, it was observed that the subjects had consumed the study drug either with water or with milk. The subanalysis was conducted for further investigation, which showed that the increase in 25(OH)D levels was statistically significant both when consumed with water or milk. Though the 25(OH)D levels increased better when consumed with milk, no statistically significant difference was observed. Further follow-up and evaluation of regular supplementation for sustained improvement in 25(OH)D levels is required. Other limitations of the present study are that the subjects were not on controlled diet, lifestyle, sun exposure, etc. Conclusion The deficiency of vitamin D is highly prevalent (>95%) in urban healthy adult population. The administration of vitamin D3 granules in the initial rapid restoration phase of 60,000 IU/week for eight weeks led to optimizing of the 25(OH)D levels. There is a need for trials of longer duration of treatment, to evaluate the effect of different lifestyle factors in this population.

Acknowledgments The study was financially supported by Abbott Healthcare Pvt. Ltd., Mumbai. Note: D3UP samples were provided by Abbott Healthcare Pvt. Ltd., Mumbai.

References 1. Harinarayan CV, Joshi SR. Vitamin D status in India - its implications and remedial measures. J Assoc Physicians India 2009;57:40-8. 2. Khan QJ, Fabian CJ. How I treat vitamin D deficiency. J Oncol Pract 2010;6(2):97-101. 3. Marwaha RK, Tandon N, Garg MK, Kanwar R, Narang A, Sastry A, et al. Vitamin D status in healthy Indians aged 50 years and above. J Assoc Physicians India 2011;59: 706-9. 4. Prentice A, Goldberg GR, Schoenmakers I. Vitamin D across the lifecycle: physiology and biomarkers. Am J Clin Nutr 2008;88(2):500S-506S.

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Internal Medicine 5. Cigolini M, Iagulli MP, Miconi V, Galiotto M, Lombardi S, Targher G. Serum 25-hydroxyvitamin D3 concentrations and prevalence of cardiovascular disease among type 2 diabetic patients. Diabetes Care 2006;29(3):722-4. 6. Lips P. Worldwide status of vitamin D nutrition. J Steroid Biochem Mol Biol 2010;121(1-2):297-300. 7. Zargar AH, Ahmad S, Masoodi SR, Wani AI, Bashir MI, Laway BA, et al. Vitamin D status in apparently healthy adults in Kashmir Valley of Indian subcontinent. Postgrad Med J 2007;83(985):713-6. 8. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al; Endocrine Society Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011;96(7):1911-30.

9. Grant WB, Holick MF. Benefits and requirements of vitamin D for optimal health: a review. Altern Med Rev 2005;10(2):94-111. 10. Malhotra N, Mithal A. Vitamin D status in Asia. International Osteoporosis Foundation. Available at: http://www.iofbonehealth.org/sites/default/files/PDFs/ Vitamin_D_Asia.pdf 11. Malhotra N, Mithal A, Gupta S, Shukla M, Godbole M. Effect of vitamin D supplementation on bone health parameters of healthy young Indian women. Arch Osteoporos 2009;4(1-2):47-53. 12. Goswami R, Gupta N, Ray D, Singh N, Tomar N. Pattern of 25-hydroxy vitamin D response at short (2 month) and long (1 year) interval after 8 weeks of oral supplementation with cholecalciferol in Asian Indians with chronic hypovitaminosis D. Br J Nutr 2008;100(3):526-9.

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Internal Medicine

A Rare Presentation of Osler-Weber-Rendu Disease as Severe Anemia Kailash Chandra Nayak*, Ashish Gupta**, Varun K**, Ashwani K Vyas**, Surendra Kumar†, Parul Prakash‡

Abstract Hereditary hemorrhagic telangiectasia (HHT) or Osler-Weber-Rendu disease is a rare fibrovascular dysplasia that makes vascular walls vulnerable to trauma and rupture causing skin and mucosal bleeding. It is of autosomal dominant inheritance characterized by recurrent epistaxis and telangiectasia on the face, hands and oral cavity; visceral arteriovenous malformations (AVMs) and positive family history. Epistaxis is often the foremost manifestation. It is associated with AVMs in several organs. There are possible hematologic, neurologic, pulmonary, dermatologic and gastrointestinal complications. Treatment is supportive and helps prevent complications. We report herein a patient with this syndrome who came to Medicine Unit first at our hospital.

Keywords: Hereditary hemorrhagic telangiectasia, arteriovenous malformations, epistaxis Case history

Investigations

A 45-year-old man born to nonconsanguineous parents presented with multiple red raised lesions on the tongue since 20 years. He came with complaints of recurrent epistaxis since 20 years and generalized weakness. He also complained of breathlessness on exertion and easy fatigability since 10 years. There was no history of any spontaneous bleeding from tongue.

ÂÂ

Peripheral blood film: Microcytic hypochromic anemia

ÂÂ

Reticulocyte count: 2%

ÂÂ

Ultrasonography (USG): Mild hepatomegaly

ÂÂ

Computed tomography (CT) scan: Left occipital infarct

ÂÂ

Upper gastrointestinal (GI) endoscopy: Normal study

Past history: The patient had undergone surgery for spontaneous pyloric perforation 10 years back. He had developed left-sided hemiparesis 10 years back, which has progressively improved since then. There is no history of bleeding gum, abdominal pain, bleeding rectum, headache, seizures, visual disturbances, hemoptysis or bluish discoloration of fingers or nose. A similar history was present in seven of his current family members. His father died from hemorrhagic shock after developing severe epistaxis. Clinical examination: Pallor +++, absence of organomegaly, multiple erythematous nonpulsatile papulonodular lesions on tongue and multiple petechiae over palate present.

*Professor **Resident †Associate Professor Dept. of Medicine ‡Assistant Professor Dept. of Obstetrics and Gynecology, SP Medical College, Bikaner, Rajasthan Address for correspondence Dr Surendra Kumar H-2, PBM Hospital Campus, Bikaner - 334 003, Rajasthan E-mail: drsurendrakumar@rediffmail.com

Discussion While Henri Rendu (1896), Sir William Osler (1901) and Frederick Parkes Weber (1907) emphasized and published detailed observations of the syndrome which bears their names, it was Sutton (1864) who first described OslerWeber-Rendu disease and Benjamin Guy Babington (1865) was the first to note its familial nature. A number of variants of hereditary hemorrhagic telangiectasia (HHT) have been described in literature. HHT type 1 (HHT1) and HHT type 2 (HHT2) are due to defective endoglin (ENG) and activin receptor-like kinase 1 (ALK1) genes, respectively. Mutations of ENG are located on the long arm of chromosomes 9 (9q33-34), whereas ALK1 mutations are on the long arm of chromosome 12 (12q13). HHT type 3 (HHT3) involves mutations of chromosome 5 (5q31p-32) and HHT type 4 (HHT4) maps on short arm of chromosome 7 (7p14). An HHT-juvenile polyposis overlap syndrome due to mutations of SMAD4 has also been described. Patients with HHT1 genotype have higher prevalence of pulmonary and cerebral arteriovenous malformations (AVMs) and more severe GI bleeding than in those with

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833

Internal Medicine

Figure 1. Patient with multiple telangiectasias on tongue and palate.

HHT2 genotype. Conversely, the prevalence of hepatic AVMs is higher in patients with HHT2. Although the precise mechanism remains poorly understood, bleeding tendency in HHT is attributed to localized vessel wall weakness. Diagnosis depends on the presence of four components known as the Curacao criteria established in June 1999 by the Scientific Advisory Board of the HHT Foundation International, Inc. These four criteria are: ÂÂ

Epistaxis: Spontaneous and recurrent

ÂÂ

Telangiectasias: Multiple, at characteristic sites including lips, oral cavity, fingers and nose

ÂÂ

Presence of internal lesions: GI telangiectasia, pulmonary, hepatic, cerebral and spinal AVMs

ÂÂ

Family history: First-degree relatives with HHT according to these criteria.

The diagnosis is unlikely if less than two criteria are present. Our case fulfilled all four criteria. His symptomatology was attributed to anemia resulting from frequent bleeding from the vascular lesions. The varied treatment modalities include estrogen, L-aminocaproic acid, cryotherapy, cautery, infrared coagulation, radiofrequency, pulse dye laser, Nd-YAG laser and surgical ablation, all of which may be fraught with risk. Asymptomatic pulmonary and central nervous system AVMs and their hemorrhagic or embolic complications viz. brain abscess and stroke are responsible for most of 10% mortality rate associated with HHT. It is crucial that a long-term follow-up for identification of potential complications is maintained and patients are counseled regarding the autosomal dominant nature of the condition. Conclusion Though cases have been reported with digital and mucocutaneous telangiectasia, our case is particularly unique as it had all the four criteria for diagnosis and also nine members of the same family could be identified with the disease.

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Suggested Reading 1. Guttmacher AE, Marchuk DA, White RI Jr. Hereditary hemorrhagic telangiectasia. N Engl J Med 1995;333(14):918-24. 2. Gu Y, Jin P, Zhang L, Zhao X, Gao X, Ning Y, et al. Functional analysis of mutations in the kinase domain of the TGF-beta receptor ALK1 reveals different mechanisms for induction of hereditary hemorrhagic telangiectasia. Blood 2006;107(5):1951-4. 3. Shovlin CL, Hughes JM, Scott J, Seidman CE, Seidman JG. Characterization of endoglin and identification of novel mutations in hereditary hemorrhagic telangiectasia. Am J Hum Genet 1997;61(1):68-79. 4. Cole SG, Begbie ME, Wallace GM, Shovlin CL. A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5. J Med Genet 2005;42(7):577-82. 5. Bayrak-Toydemir P, McDonald J, Akarsu N, Toydemir RM, Calderon F, Tuncali T, et al. A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7. Am J Med Genet A 2006;140(20):2155-62. 6. Gallione CJ, Repetto GM, Legius E, Rustgi AK, Schelley SL, Tejpar S, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet 2004;363(9412):852-9. 7. Johnson DW, Berg JN, Baldwin MA, Gallione CJ, Marondel I, Yoon SJ, et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 1996;13(2):189-95. 8. Shovlin CL, Guttmacher AE, Buscarini E, Faughnan ME, Hyland RH, Westermann CJ, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-OslerWeber syndrome). Am J Med Genet 2000;91(1):66-7. 9. Saba HI, Morelli GA, Logrono LA. Brief report: treatment of bleeding in hereditary hemorrhagic telangiectasia with aminocaproic acid. N Engl J Med 1994;330(25):1789-90. 10. Colver GB, Davies S, Bullock J. Infrared coagulation for bleeding mucosal telangiectasia. J Laryngol Otol 1992;106(11):992-3. 11. Jovancević L, Mitrović SM. Epistaxis in patients with hereditary hemorrhagic telangiectasia. Med Pregl 2006;59(9-10):443-9. 12. Harries PG, Brockbank MJ, Shakespeare PG, Carruth JA. Treatment of hereditary haemorrhagic telangiectasia by the pulsed dye laser. J Laryngol Otol 1997;111(11):1038-41.

Neurology

Multiple Myeloma Presenting as Acute Hemiplegia due to Space Occupying Lesion: A Case Report SHWETA SAHAI*, ATUL SAHAI**

Abstract Acute onset hemiplegia is an extremely rare presentation of multiple myeloma (MM). In most of these cases, the onset of hemiplegia is due to stroke caused by hyperviscosity secondary to the paraproteinemia in MM. Hemiplegia secondary to intracranial plasmacytoma is one of the rarest presentations of MM. We present here the case of a woman who reported with acute onset hemiplegia secondary to intracranial space occupying lesion, which proved to be plasmacytoma.

Keywords: Myeloma, plasmacytoma

patient of multiple myeloma (MM) usually presents with features of skeletal involvement like bony pains, pathological fractures, etc. Anemia, signs of renal failure and increased susceptibility to infections may be other common presentations. Neurological manifestations occur in a small minority of patients of MM and are usually late manifestations during the course of the disease. They are mostly caused by skeletal infiltration of the vertebra causing spinal cord or nerve root compression. Peripheral neuropathy may occur due to presence of antibodies against myelin structures or due to amyloid deposits. Hemiplegia, if occurring during the course of MM, may by due to stroke caused by paraproteinemia leading to hyperviscosity, or due to intracranial plasmacytoma. However, neurological presentation in MM due to plasmacytomas located intracranially is extremely rare. Plasmacytoma is a rare entity, of which two variants have been described:

ÂÂ

Solitary bone plasmacytoma (SBP): This is defined as a single, lytic bone lesion without marrow plasmacytosis. This variety is commoner in occurrence intracranially.

*Assistant Professor, Dept. of Medicine, Gajra Raja Medical College, Gwalior, MP **Consultant Neurosurgeon, Birla Institute of Medical Research, Gwalior, MP Address for correspondence Dr Shweta Sahai 42, Sharda Vihar, Near New High Court, City Centre, Gwalior, MP E-mail: Sahay.shweta2@gmail.com, Sahai_2004@yahoo.co.in

ÂÂ

Soft-tissue extramedullary plasmacytoma (SEP): In this variety, submucosal lymphoid tissue of the nasopharynx or paranasal sinuses usually manifests as a growth.

The common features amongst the two varieties is that there is little or no bone marrow plasmacytosis (bone marrow plasma cell count <5%) and they are highly sensitive to radiotherapy. SBP is more likely to progress to MM (>70% at 10 years after diagnosis) than SEP (20% at 10 years after diagnosis). Hence, plasmacytoma is considered to be part of the disease spectrum of MM. CASE REPORT A 65-year-old woman was admitted to our hospital with acute onset hemiplegia of the right side. There were no preceding symptoms of headache, vomiting or convulsions. Examination showed a normal pulse and blood pressure. She had bilateral papilledema. The power was Grade 0 on the right side. There was no sensory loss. She had suffered a fracture of the left humerus when she fell down at the onset of hemiplegia. Investigations revealed a normal hemogram and routine biochemical tests. Computed tomography (CT) scan of the head revealed a hyperdense, densely enhancing, extracerebral mass lesion in the left parieto-occipital region. Its extension was seen outside the cranium. The CT also revealed multiple lytic lesions in all the cranial bones. On shaving of her head, the growth was

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835

Neurology 1995 and 2004, only 30 cases could be found. Montalban et al4 have reported an unusual case of MM with cranial nerve neuropathy due to intracranial plasmacytoma. Tanaka et al5 have reported a case of solitary plasmacytoma of the skull and noted that only 35 cases have been reported in English literature. Wavre et al6 have reported a case of intracerebral plasmacytoma as an initial presentation of MM and have noted that diagnosis of MM subsequent to initial cerebral involvement is confined to exceptional cases. In fact, CNS involvement in MM is usually a late feature. The median interval from diagnosis of MM to detection of CNS involvement tends to be around 13-14 months. Figure 1. CT scan of the head showing a hyperdense, densely enhancing, extracerebral mass lesion in the left parietooccipital region.

visible from outside the skull. Fine-needle aspiration cytology (FNAC) was done, which revealed features of plasmacytoma. Subsequently, a whole body bone scan was done, which revealed multiple lytic lesions in the skeleton, including that of the left humerus, which had caused the pathological fracture. Serum electrophoresis revealed M-spike on a polyclonal gamma background. Bone marrow examination showed a plasma cell infiltration of 10%. DISCUSSION Neurological symptoms as initial presentations have been described in MM as case reports due to their rarity. The overall incidence of central nervous system (CNS) involvement in MM has been reported to be 1%. Most of the reported cases have been of stroke-like presentations due to cerebral infarction caused by hyperviscosity. Dey et al1 have reported a case of MM presenting as recurrent right middle cerebral artery (MCA) stroke due to hyperviscosity syndrome. Park et al2 and Perez-Diaz et al3 have also reported cases of MM presenting as stroke. Intracranial plasmacytomas leading to neurological presentations in MM have been found to be extremely rare. In a MEDLINE search between

CONCLUSION Cerebral involvement is rare in cases of MM. When it does occur, it is usually a late feature and is often a result of cerebral infarction due to hyperviscosity. This case warrants reporting on account of the exceptionally rare presentation of MM presenting initially as hemiplegia due to intracerebral space occupying lesion. REFERENCES 1. Dey AB, Nagarkar K, Kumar V. Multiple myeloma presenting as recurrent stroke. J Assoc Physicians India 1996;44(11):832-3. 2. Park MS, Kim BC, Kim IK, Lee SH, Choi SM, Kim MK, et al. Cerebral infarction in IgG multiple myeloma with hyperviscosity. J Korean Med Sci 2005;20(4):699-701. 3. Pérez-Díaz H, Serrano-Pozo A, González-Marcos JR. Multiple myeloma as a treatable cause of stroke: clinical case and review of the literature. Neurologia 2007;22(1): 54-7. 4. Montalban C, Martín-Aresti J, Patier JL, Millan JM, Cosio MG. Unusual cases in multiple myeloma and a dramatic response in metastatic lung cancer: Case 3. Intracranial plasmacytoma with cranial nerve neuropathy in multiple myeloma. J Clin Oncol 2005;23(1):233-5. 5. Tanaka M, Shibui S, Nomura K, Nakanishi Y. Solitary plasmacytoma of the skull: a case report. Jpn J Clin Oncol 1998;28(10):626-30. 6. Wavre A, Baur AS, Betz M, Mühlematter D, Jotterand M, Zaman K, et al. Case study of intracerebral plasmacytoma as an initial presentation of multiple myeloma. Neuro Oncol 2007;9(3):370-2.

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Obstetrics and Gynecology

Uterovaginal Prolapse with Giant Vesical Calculus: A Rare Case Report Shashidhar B*, Krishna Shetty**

Abstract Massive or giant vesical calculus is a rare entity in urological practice. Females are less affected than males. Vesical calculi are usually due to long-standing uterovaginal prolapse and bladder outlet obstruction coupled with chronic infection. These patients present with recurrent urinary tract infection (UTI), hematuria or with retention of urine. We report a case of 50-yearold female, who presented with history of mass per vagina and recurrent UTI. Her renal function tests were normal and urine examination showed infection. Plain X-ray showed a large radio-opaque calculus in pelvic region. Ultrasound pelvis reported a large freely mobile vesical calculus 9 x 11 cm with bilateral hydroureteronephrosis, which was more pronounced on left side than right. After controlling UTI, she underwent an open suprapubic cystolithotomy and total abdominal hysterectomy and bilateral salpingo-oophorectomy. Postoperative stay was uneventful and she was discharged on 10th postoperative day. Patient is still on follow-up with good urinary function and no recurrent UTI.

Keywords: Giant vesical calculus, uterovaginal prolapse

he association of giant vesical calculi and uterovaginal prolapse is an uncommon entity.1,2 Vesical calculus weighing >100 g is an unusual finding in modern urological practice. Long-standing uterovaginal prolapse and bladder outlet obstruction, coupled with chronic infection are suspected to be the causative factors. Anatomic findings usually associated with vesical calculus are cystocele, enterocele of uterovaginal prolapse or findings of prior urethral surgery all of which contribute to elevated residual urine. In cases of acute irreducible pelvic organ prolapsed or incarcerated procidentia, the possibility of bladder stones should be confirmed by X-ray pelvis including the prolapsed mass.3,4 We report herein a case of a rare association of uterovaginal prolapse with giant vesical calculi. Case report A 50-year-old female patient with postmenopausal status of five years, presented with complaints of mass *Assistant Professor Dept. of Obstetrics and Gynecology **Professor Dept. of Urology, Sri Devraj Urs Medical College, Tamaka, Kolar, Karnataka Address for correspondence Dr Shashidhar B Assistant Professor Dept. of Obstetrics and Gynecology Sri Devraj Urs Medical College, Tamaka Kolar - 563 101, Karnataka E-mail: shashi0328@gmail.com

per vagina since three years and dysuria for six months relieved with treatment off and on to recur again. She was never subjected to any type of investigation. She has been married for 25 years with three children. All the deliveries were full term at home. On examination, she was moderately built and nourished. Local examination revealed a seconddegree uterine descent with first-degree cystocoele. Her investigations showed hemoglobin 12 g/dl, blood urea 25 mg/dl, serum creatine 1.3 mg/dl, sodium 148 mEq/l, potassium 41 mEq/l, chloride 102 mEq/l; blood sugar levels were within normal limits. Urine examination showed plenty of white blood cells (WBCs) and epithelial cells. Pap smear was positive for Gardnerella vaginalis. Ultrasound pelvis reported a large freely mobile vesical calculus of size 9 x 11 cm with bilateral hydroureteronephrosis, which was more pronounced on left side than right. Urinary bladder wall thickened to 8 mm with mucosal irregularity. Plain X-ray showed a large radio-opaque calculus in the pelvic region. Urine culture sensitivity reported growth of Citrobacter koseri and significant bacteriuria sensitive to third-generation cephalosporins, imipenems, amikacin and metronidazole. A suprapubic cystolithotomy was performed and stone was extracted, followed by abdominal hysterectomy with bilateral salpingooophorectomy. The calculus weighed 475 g and measured 9.5 x 11 cm. The urinary bladder was closed in two layers. Postoperative stay was uneventful and she was discharged on 10th postoperative day.

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Figure 1. KUB showing vesical calculus.

Figure 4. Giant vesical calculus. Four weeks later a repeat abdominopelvic ultrasound revealed normal study with completely resolved hydroureteronephrosis. Patient is still on follow-up with good urinary function and no recurrent urinary tract infection (UTI). Discussion

Figure 2. Calculus seen through the bladder incision.

Figure 3. Calculi being delivered out.

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An urinary bladder stone is usually defined as a giant calculus when its weighs >100 g. Urinary bladder calculi constitute 5% of all urolithiasis. The incidence of female urinary lithiasis is very low; 95% of all bladder stones occur in men. The maleto-female ratio is approximately 3:1. Long-standing prolapse and bladder outlet obstruction, coupled with chronic infection are suspected to be the inciting factors. Cases of vesical calculus resulting in azotemia and retention of urine and obstructive uropathy have been reported.5,6 Few cases of vesical calculi causing mechanical dystocia during labor, recurrent cystitis for over a decade and vesicovaginal fistula has been reported in literature.7-9 The initial imaging study of choice is plain radiography of the kidneys, ureters and bladder (KUB) because it is the least expensive and easiest radiologic test to obtain. A radiograph of the pelvis, including the prolapsed tissues is warranted in the preoperative work-up in patients with incarcerated procidentia. With the widespread availability of ultrasonography, this relatively inexpensive and rapid modality can be more widely used to diagnose bladder calculus. The sonogram showing a classic hyperechoic object

Obstetrics and Gynecology with posterior shadowing is effective in identifying both radiolucent and radio-opaque stones. Computed tomography (CT) scan is usually obtained for other reasons (e.g., abdominal pain, pelvic mass, suspected abscess) but may demonstrate bladder calculi when performed without intravenous contrast. Magnetic resonance imaging (MRI) is an expensive imaging modality that yields poor resolution of calculi. It is not recommended in the evaluation of bladder calculi. Open surgery has been the best recommended modality for large stones. Suprapubic percutaneous lithotripsy has complete stone clearance in adults though the procedure takes a long time; stone clearance is complete. Conclusion Nephrolithiasis occurs in all parts of the world with a lower lifetime risk of 2-5% in Asia, 8-15% in the West and 20% in Saudi. This article aims to enable all practitioners to be able to recognize the condition and instigate early investigation and management before referring to the urologist for definitive treatment. Because obstructive lesions and infection seem to play a role in the formation and growth of vesical calculi, early treatment will minimize the occurrence of stones.

References 1. Singal R, Goyal S, Sekhon MS, Pandit S. A rare giant urinary bladder stone: a case report. Urotoday Int J 2010;3(3). 2. Johnson CG. Giant calculus in the urinary bladder associated with complete uterine prolapse; report of a case. Obstet Gynecol 1958;11(5):579-80. 3. Siriwardana PN, Gunasekara M. Multiple vesical calculi in a cystocele: an uncommon complication of procidentia. J Pelvic Med Surg 2008;14(3):207-8. 4. Dahiya P, Gupta A, Sangwan K. Multiple bladder calculi: a rare cause of irreducible uterine prolapse. Arch Gynecol Obstet 2007;275(5):411-2. 5. Kang LM, Liu CH, Huang Cl, Lee MG. Uterine prolapse results in vesical stones, ureteral stone, and acute renal failure: a case report. Journal of Urology ROC 2000;11(4):190-2. 6. Rege SA, Nunes QM, Dalvi AN. Giant vesical calculus. Bombay Hospital Journal 2001;43(4):582-3. 7. Ait Benkaddour Y, Aboulfalah A, Abbassi H. Bladder stone: uncommon cause of mechanical dystocia. Arch Gynecol Obstet 2006;274(5):323-4. 8. Lin WY, Wu CF, Shee JJ, Chen CS. A decade of recurrent cystitis in a woman due to a giant vesical calculus. Int Urogynecol J Pelvic Floor Dysfunct 2006;17(6):674-5. 9. Deshmukh SN, Maske AN, Deshpande AP, Shende SP. Vesicocutaneous fistula caused by giant vesical calculus. Indian J Surg 2011;73(2):152-4.

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Time Limit of Abortions Raised to Nine Weeks The time limit for abortions has been increased from 7 to 9 weeks to facilitate family planning, the Drug Controller General of India has said. Nozer Sherian, secretary general of the Federation of Obstetric and Gynaecological Societies (FOGSI), said here Friday: "The Drug Controller General has increased the time limit of abortions to 63 days, that is nine weeks." In the last two years, 3,32,000 medical abortions were carried out, which show that if given a choice, women want to limit their families. "This is very important as around eight percent of maternal deaths take place due to unsafe abortions," he said. FOGSI is promoting medical abortions along with Intrauterine Medical Devices (IUD) to help people plan their families. Hema Diwakar, president of FOGSI, said that women are now given a choice of post-placental IUD as soon as they give birth. The family planning initiative taken up by the FOGSI and the Population Services International (PSI) is called 'Pehel'. It is run mostly in urban slums. It covers 30 districts in Rajasthan, Uttar Pradesh and Delhi. Ten additional districts in these three states would be covered in the next phase. "Pehel Phase 3 will continue to complement the government's efforts to reduce maternal mortality and increase the contraceptive prevalence rate," said Pritpal Marjara, director of PSI. According to government data, every year about 78,000 women die during pregnancy, child birth or within 43 days of delivery in India. (Source: The Pioneer, 26 April 2013).

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Ovarian Fibrothecoma with Extensive Cystic Degeneration: Two Case Reports Suprabha Sharma*, R Bansal**, Sanjay Upreti†, Anjali Khare‡, Sangeeta Sharma*, Deepti Agarwal†

Abstract Two females aged 70 years and 45 years presented in OPD of Dept. of Gynecology with large abdominal lump and ascites. In both cases, clinical and radiological diagnosis of malignant ovarian tumor was made. Ascitic fluid cytology revealed absence of malignant cells. Panhysterectomy was performed. On histopathological examination, both cases were diagnosed as benign fibrothecoma with extensive cystic change. Postoperative follow-up for about six months was uneventful and both patients recovered completely.

Keywords: Ovarian fibrothecoma, cystic degeneration

ibrothecomas of ovary constitute a group of benign tumors arising in stroma and exhibit a morphological spectrum from those composed of entirely fibroblasts and producing collagen (Fibromas) to those containing more plump spindle cells with lipid droplets (Thecomas). When a tumors contains mixture of these cells, they are termed as fibrothecomas described as rare ovarian neoplasm. These tumors constitute about 4% of all ovarian tumors. We report two cases whose clinical presentations were highly deceptive and were clinically and radiologically diagnosed as malignant ovarian tumor with peritoneal metastases. Histopathologically, ovarian fibrothecomas frequently show focal or partial cystic degeneration. However, extensive cystic degeneration is not common in fibrothecomas. Case No. 1

ovarian tumor. Panhysterectomy and omentectomy were performed. Gross examination: A multinodular cystic tumor of the right ovary about 20 x 10 cm was identified. On cut section, hemorrhagic fluid came out. Solid and cystic areas with yellowish bands were present in the solid part (Fig. 1). Uterus, cervix, left ovary and both tubes were unremarkable. Microscopic examination: Interlacing bands and storiform pattern of elongated spindly cells containing scanty to moderate amount of eosinophilic to clear cytoplasm were seen. Collagenized and hyalinized stroma and focal collections of plump cells with clear cytoplasm were seen. Cystic areas showed similar tumor tissue without definite cyst lining. Areas of hemorrhage and edema were present. On special staining, it was positive for Vimentin, which is a characteristic feature of ovarian fibrothecoma.

A 70-year-old female presented with large abdominal lump of 20 weeks size with ascites. It was nontender, freely mobile and about 21 cm in diameter. Hematological and biochemical parameters were within normal range. Ultrasonography revealed a large multiloculated globular cystic mass of 20 x 10 cm size with fluid in abdominal cavity. Radiological and preoperative clinical diagnosis was malignant

*Associate Professor **Professor and Head †Assistant Professor ‡Professor Dept. of Pathology, Subharti Medical College Subhartipuram, Meerut, UP

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Figure 1. Cut surface of ovary having solid grayish white areas (thin arrow) with cystic change (thick arrow).

Obstetrics and Gynecology Case No. 2 A 45-year-old female presented with a painful mass and distension in lower abdomen for few months. Routine hematological and biochemical investigation were within normal limits except for an elevated level of cancer antigen (CA)-125 (200 U/ml). Ultrasonography (USG) showed multiloculated globular mass with cystic and solid areas at the periphery of the mass. Associated changes in uterus such as enlargement and endometrial thickening were not observed. Panhysterectomy was performed. Gross examination: A huge nodular focally congested right ovarian mass of 15 x 8 x 6 cm size was received. Cut surface showed solid grayish white to yellowish areas with few cystic and solid granular areas. Microscopic examination: Tumor tissue showed bundles of elongated spindle cells having oval uniform nuclei. At places, few cells appeared foamy. Focal areas of cystic degeneration and edema were evident. No capsular infiltration was seen. The final histopathological diagnosis was ovarian fibrothecoma with cystic degeneration (Fig. 2). Discussion The ovarian fibroma, thecoma and fibrothecoma are the rare benign tumors growing from the connective tissue of ovarian cortex. These account for about 4% of all ovarian tumors. The clinical presentation of ovarian fibrothecoma is relatively nonspecific such as pelvic and abdominal pain or distension; however, ovarian fibromas may be accompanied by two associations. The first is called Meigâ&#x20AC;&#x2122;s syndrome (ovarian fibroma, hydrothorax and ascites). The second association is with basal cell nevus syndrome (bilateral ovarian fibromas, multiple basal cell carcinoma of skin, odontogenic keratocysts, etc.) Our both cases diagnosed as fibrothecoma were associated only with ascites. Some ovarian thecomas are hormonally active, showing estrogenic manifestations such as irregular bleeding, amenorrhea, endometrial hyperplasia and endometrial carcinoma. However, in the present cases no such abnormality was observed. Grossly, ovarian fibrothecomas are unilateral in about 90% of all cases and are usually solid, spherical or slightly lobulated, encapsulated hard gray white masses covered by glistening and intact ovarian serosa. Ovarian fibrothecomas of a large size tend to be associated with varying degree of edema, myxoid change and cystic degeneration but ovarian fibrothecomas showing extensive cystic degeneration

Figure 2. H&E (40x) photomicrograph of fibrothecoma, showing thecal cells (thin arrow) and fibrous component (thick arrow).

as in present cases are unusual. The mechanism of extensive cystic degeneration is unclear. Samanth et al reported that ovarian tumors of fibrothecoma group >10 cm in diameter tend to be associated with myxoid change or degeneration and insisted that a discrepancy between arterial supply and venous and lymphatic drainage could lead to intramural stromal edema. Other investigators have commented on the protean nature of ovarian tumor in this group that may be the cause of edema and elevated CA-125. However, one of our cases showed elevated CA-125, which further complicated the clinical diagnosis though fibrothecomas with elevated CA-125 have been reported previously. Conclusion The granulosa theca cell tumor is probably the most inaccurately diagnosed lesion of the female gonad, clinically as well histologically. The accurate preoperative diagnosis of ovarian fibrothecomas with cystic degeneration could have prevented the extensive surgical intervention such as bilateral salpingooophorectomy with hysterectomy. Suggested reading 1. Sills ES, Doan TB, Mock RJ, Dixson GR, Rohlfing MB. Immunohistochemical localization patterns for vimentin and other intermediate filaments in calcified ovarian fibrothecoma. Diagn Pathol 2006;1:28. 2. Takeshita T, Shima H, Oishi S, Machida N, Yamazaki K, Imamura T, et al. Ovarian fibroma (fibrothecoma) with extensive cystic degeneration: unusual MR imaging findings in two cases. Radiat Med 2005;23(1):70-4. 3. Samanth KK, Black WC 3rd. Benign ovarian stromal tumors associated with free peritoneal fluid. Am J Obstet Gynecol 1970;107(4):538-45.

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Osteoporosis: Current Management Guidelines Harmanjit Singh*, Manoj Goyal**, Jasbir Singh†

Abstract Osteoporosis is a multifactorial progressive skeletal disorder characterized by reduced bone mass and deterioration of bone microarchitecture. Fragility fractures, the consequence of osteoporosis, are responsible for excess mortality, morbidity, chronic pain, admission to hospitals and economic costs. Approximately 1.6 million hip fractures occur each year worldwide and the incidence is set to increase to 6.3 million by 2050. Preventive measures should be started at an early age and should include smoking cessation and weight-bearing exercises. Pharmacologic prevention methods include calcium supplementation and administration of raloxifene or bisphosphonates. No treatment can completely reverse established osteoporosis. Early intervention can prevent osteoporosis in most people. For patients with established osteoporosis, medical intervention can halt its progression. Currently available therapies include bisphosphonates, selective estrogen receptor modulators (SERMs), hormone replacement therapy (HRT), denosumab, teriparatide, calcitonin and strontium ranelate. Cathepsin K inhibitors (balicatib and odanacatib) are among recent drugs under development. Saracatinib, a novel orally available competitive inhibitor of Src kinase has been shown to inhibit bone resorption in vitro. Lasofoxifene, bazedoxifene and arzoxifene are new SERMs in late-stage treatment trials. Nonpharmacological measures are required when patients experience adverse effects because of drug therapy, when symptoms are not controlled by drug therapy alone or when patient is not willing to take drugs for a prolonged duration.

Keywords: Fragility fractures, bisphosphonates, SERMs, Src kinase

steoporosis is a multifactorial progressive skeletal disorder characterized by reduced bone mass and deterioration of bone microarchitecture, predisposing it to increased fracture risk. Osteoporosis is called a ‘silent disease’ because it progresses without symptoms and remains unnoticed for a long time as bone resorption process in early stages is almost asymptomatic and at later stages usually presents with a fracture due to trivial trauma.1 Fragility fractures, the consequence of osteoporosis, are responsible for excess mortality, morbidity, chronic pain, admission to institutions and economic costs. They represent 80% of all fractures in menopausal women over age 50. Patients with hip or vertebral fractures have substantially increased risk of death after the fracture. With major improvements in diagnostic technology and assessment facilities; it is now possible to detect the disease before fractures occur. Once the condition

*Senior Resident Dept. of Pharmacology, PGIMER, Chandigarh **Associate Professor Dept. of Pharmacology, MMIMSR, Mullana, Haryana †Lecturer Dept. of Pharmacology, GMC, Patiala Address for correspondence Dr Harmanjit Singh Dept. of Pharmacology, PGIMER, Chandigarh E-mail: harman_gmcp@yahoo.com

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is diagnosed, steps can be taken to prevent further damage, including special exercises, changes in the diet, lifestyle changes and supplements or medication. Burden of Osteoporosis According to various surveys, worldwide one in 3 women over 50 will suffer a fracture due to osteoporosis; this increases to one in 2 in women over 60. One in 5 men over 50 will suffer a fracture due to osteoporosis; this increases to one in 3 over 60. Approximately 1.6 million hip fractures occur each year worldwide and the incidence is set to increase to 6.3 million by 2050.2 Currently and there is an increasing incidence of hip fractures in the developed cities in Asia. One out of 4 hip fractures occur in Asia and Latin America.3 Osteoporosis is also becoming a serious public health problem in India. Conservative estimates in a study suggest that 20% of women and about 10-15% of men are osteoporotic in India.4 Another highly conservative estimate by a group of experts suggested that 26 million Indians suffer from osteoporosis, and this number is expected to reach 36 million by 2013.5 WHO definition of Osteoporosis6 The World Health Organization (WHO) operationally defines osteoporosis as a bone density that falls 2.5

Orthopedics standard deviations (SD) below the mean for young healthy adults of the same sex - also referred to as a T-score of –2.5. Postmenopausal women who fall at the lower end of the young normal range (a T-score ≤1.0) are defined as having low bone density and are also at increased risk of osteoporosis. More than 50% of fractures among postmenopausal women, including hip fractures, occur in this group with low bone density. The WHO definition applies to postmenopausal women and men aged 50 years or older. This diagnostic classification should not be applied to premenopausal women, men younger than 50 years or children. Bone mineral density (BMD) in a patient is related to peak bone mass and subsequently, bone loss. The T-score is the patient’s bone density compared with the BMD of control subjects who are at their peak BMD, while the Z-score reflects a bone density compared with that of patients matched for age and sex. Several noninvasive techniques are available for estimating skeletal mass or density. They include dualenergy X-ray absorptiometry (DXA), single-energy X-ray absorptiometry (SXA), quantitative computed tomography (CT) and ultrasound (US). DXA is a highly accurate X-ray technique that has become the standard for measuring bone density in most centers.7 Pathophysiology Osteoporosis is classified as ‘primary’ and ‘secondary’. Primary osteoporosis by convention is of relatively unknown origin that occurs with aging and accelerates with menopause or andropause. There is no direct or singular cause for primary osteoporosis but there are several clinical risk factors (Table 1). Secondary osteoporosis is the consequence of conditions such as hormonal imbalances, diseases or medications. It is increasingly being recognized that multiple pathogenetic mechanisms operate in the development of the osteoporotic state. The hallmark of osteoporosis is a reduction in skeletal mass caused by an imbalance between bone resorption and bone formation. Under physiologic conditions, bone formation and resorption are in a fair balance. A change in either that is, increased bone resorption or decreased bone formation may result in osteoporosis. Osteoclasts derived from mesenchymal cells are responsible for bone resorption, whereas osteoblasts from hematopoietic precursors are responsible for bone formation. These two types of cells are dependent on each other for production and linked in the process of bone remodeling. Osteoblasts not only secrete and

mineralize osteoid but also appear to control the bone resorption carried out by osteoclasts. Osteocytes, which are terminally differentiated osteoblasts embedded in mineralized bone, direct the timing and location of bone remodeling. In osteoporosis, the coupling mechanism between osteoclasts and osteoblasts is thought to be unable to keep up with the constant microtrauma to trabecular bone. Osteoclasts require weeks to resorb the bone, whereas osteoblasts need months to produce new bone. Osteoclasts resorbs the bone matrix by secreting hydrochloric acid, which dissolves calcium phosphate, and enzymes such as collagenase and other proteases. Therefore, any process that increases the rate of bone remodeling results in net bone loss over time. Furthermore, in periods of rapid remodeling (e.g., after menopause), bone is at an increased risk for fracture because the newly produced bone is less densely mineralized, the resorption sites are temporarily unfilled and the isomerization and maturation of collagen are impaired. The receptor activator of nuclear factor-k B ligand (RANKL)/receptor activator of nuclear factor-k B (RANK)/osteoprotegerin (OPG) system is the final common pathway for bone resorption. Osteoblasts and activated T cells in the bone marrow produce the RANKL cytokine. RANKL binds to RANK expressed by osteoclasts and osteoclast precursors to promote osteoclast differentiation. Osteoprotegerin is a soluble decoy receptor that inhibits RANK-RANKL by binding and sequestering RANKL.8,9 Risk factors Risk factors for osteoporosis, such as advanced age and reduced BMD, have been established by virtue of their direct and strong relationship to the incidence of fractures; however, many other factors have been considered risk factors based on their relationship to BMD as a surrogate indicator of osteoporosis (Table 1). Management The most important measure in the management of osteoporosis is treatment of the underlying cause. Various preventive treatment measures have been described below.

Measures to Prevent Osteoporosis Primary prevention of osteoporosis starts in childhood. Patients require adequate calcium intake, vitamin D intake and weight-bearing exercise. Beyond this, prevention of osteoporosis has two components:

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Orthopedics Table 1. Risk Factors for Osteoporosis and Drugs causing Osteoporosis10-12 Nonmodifiable

Potentially modifiable

yy Advanced age (≥50 years) yy Female sex yy White or Asian ethnicity yy Genetic factors as family history of osteoporosis yy Dementia

yy Cigarette smoking yy Low body weight (<58 kg or 127 lb) yy Recurrent falls yy Inadequate physical activity yy Estrogen deficiency yy Drugs* yy Alcohol use yy Early menopause yy Prolonged premenopausal amenorrhea yy Androgen or estrogen deficiency yy Calcium deficiency yy Poor health

*Drugs: Anticonvulsants (phenytoin, carbamazepine, phenobarbitone, valproate), heparin, lithium, chemotherapeutic agents, cyclosporine, systemic steroids, thyroxine supplements, GnRH agonist, aromatase inhibitors.

Behavior modification and pharmacologic interventions. The following behaviors should be modified to reduce the risk of developing osteoporosis: Cigarette smoking, physical inactivity and intake of alcohol, sodium, animal protein. Patients should be counseled on smoking cessation and moderated alcohol intake. Patients who have medical disorders and are on medications* (Table 1) that can cause or accelerate bone loss should receive calcium and vitamin D supplementation and in some cases, pharmacologic treatment. Exercise Exercises are another way to maintain BMD, prevent the progression of osteoporosis and reduce the risk of developing bone fractures. A combination of weightbearing and strength training exercises are most effective. Even just walking or jogging regularly can help prevent osteoporosis. A walking program is the best way to start; activities like dancing, aerobics, racquet sports, running and the use of gym equipment are also recommended, depending upon the patient’s preference and general condition. Exercise has beneficial effect on neuromuscular function, and improves coordination, balance and strength, thereby reducing the risk of falling. Weight-bearing exercises should be started at early age. Exercise habits should be consistent, at least three times a week as more substantial effect on bone mass is likely if exercise is continued over a long period of time. The beneficial effect wanes if exercise is discontinued.10-14 Pharmacologic prevention Pharmacologic prevention methods include calcium supplementation and administration of raloxifene

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or bisphosphonates (alendronate or risedronate). Bisphosphonates and raloxifene should be considered as first-line agents for the prevention of osteoporosis. Calcium supplementation: The goal of the current recommendations for daily calcium intake is to ensure that individuals maintain an adequate calcium balance. Current recommendations from the American Association of Clinical Endocrinologists (AACE) for daily calcium intake are as follows.15 ÂÂ

Age 0-6 months: 200 mg/day

ÂÂ

Age 6-12 months: 260 mg/day

ÂÂ

Age 1-3 years: 700 mg/day

ÂÂ

Age 4-8 years: 1,000 mg/day

ÂÂ

Age 9-18 years: 1,300 mg/day

ÂÂ

Age 19-50 years: 1,000 mg/day

ÂÂ

Age ≥50 years: 1,200 mg/day

ÂÂ

Pregnant and breastfeeding women ≤18 years: 1,300 mg/day

ÂÂ

Pregnant and breastfeeding women ≥19 years: 1,000 mg/day

Vitamin D supplementation: Vitamin D is increasingly being recognized as a key element in overall bone health and muscle function. It plays a significant role in bone health, calcium absorption, balance (e.g., reduction in risk of falls) and muscle performance. The minimum daily requirement in patients with osteoporosis is 800 IU of vitamin D3, or cholecalciferol. Many patients require higher levels (continuously or for a short period) to be considered vitamin D replete, which is defined as a serum 25-hydroxyvitamin D level of 32 ng/ml. Vitamin D is available as ergocalciferol (vitamin D2)

Orthopedics and cholecalciferol (vitamin D3). Vitamin D is metabolized to active metabolites. These metabolites promote the active absorption of calcium and phosphorus by the small intestine, elevating serum calcium and phosphate levels sufficiently to permit bone mineralization.16-18 Other nutrients10,11,19 ÂÂ

Adequate dietary intake of salt, animal protein.

ÂÂ

Adequate vitamin K status (required for optimal carboxylation of osteocalcin).

ÂÂ

Dietary phytoestrogens derived from soya products and legumes (exert estrogenic activity).

Pharmacotherapy of Osteoporosis Currently, no treatment can completely reverse established osteoporosis. Early intervention can prevent osteoporosis in most people. For patients with established osteoporosis, medical intervention can halt its progression. If secondary osteoporosis is present, treatment for the primary disorder should be provided. Therapy should be individualized based on each patient’s clinical scenario, with the risks and benefits of treatment discussed between the clinician and patient. The National Osteoporosis Foundation (NOF, 2010)20 recommends that pharmacologic therapy should be reserved for postmenopausal women and men aged 50 years or older who present with the following: ÂÂ

A hip or vertebral fracture (vertebral fractures may be clinical or morphometric i.e., identified on a radiograph alone)

ÂÂ

T-score of –2.5 or less at the femoral neck or spine after appropriate evaluation to exclude secondary causes

ÂÂ

Low bone mass (T-score between –1.0 and –2.5 at the femoral neck or spine) and a 10-year probability of a hip fracture of 3% or greater or a 10-year probability of a major osteoporosis-related fracture of 20% or greater based on the US-adapted WHO algorithm.

Guidelines from the AACE,15 published in 2010, include the following recommendations for choosing drugs to treat osteoporosis: ÂÂ

First-line agents: Alendronate, zoledronic acid, denosumab

risedronate,

ÂÂ

Second-line agent: Ibandronate

ÂÂ

Second- or third-line agent: Raloxifene (SERMs)

ÂÂ

Last-line agent: Calcitonin

ÂÂ

Treatment for patients with very high fracture risk

or in whom bisphosphonate therapy has failed: Teriparatide. Bisphosphonates The most commonly prescribed drugs to treat osteoporosis are bisphosphonates. Alendronate was the first bisphosphonate to be approved for treatment of osteoporosis in the US in 1995. Since that time, newer bisphosphonates with less frequent dosing intervals have been introduced, partially in an attempt to improve compliance. Risedronate is an oral medication that can be administered daily, weekly or monthly at varying doses. Zoledronic acid is the newer medication, which is administered once yearly by intravenous (IV) transfusion. Bisphosphonates bind to hydroxyapatite crystals and thus have a very high affinity for bone. Bisphosphonates are released from the bone matrix upon exposure to acid and enzymes secreted by an active osteoclast. Out of all bisphosphonates, zoledronic acid has the highest affinity for binding to the bone mineral matrix followed by pamidronate > alendronate > ibandronate > risedronate > etidronate > clodronate. Bisphosphonates with higher affinity like zoledronic acid bind avidly to the bone surface, but spread through bone slowly, whereas lower affinity agents like clodronate distribute more widely through the bone, but they have shorter time of residence when the treatment is stopped. Suppression of bone resorption occurs within approximately three months of initiation of oral bisphosphonate therapy regardless of dosing frequency, but it is more rapid after IV administration. After three years of treatment, bisphosphonates have been shown to increase BMD of the hip by 3-6% and at the spine by 5-8%. In women with osteoporosis, zoledronic acid, alendronate and risedronate also reduced nonvertebral fractures by 25-40%, including hip fractures by 40-60%.21,22 Dose: Zoledronic acid: 5 mg single IV infusion annually, alendronate: 10 mg/day orally, ibandronate: 2.5 mg oral daily or 150 mg once monthly, risedronate: 5 mg/day oral. Some important adverse events associated with bisphosphonates therapy: Orally administered bisphosphonates may cause irritation in the esophagus. It is recommended to swallow oral bisphosphonates with full glass of plain water on arising in the morning, remaining upright for at least 30 minutes after swallowing the tablet and discontinuing the drug promptly if esophageal symptoms develop. Rapid IV administration of parenteral bisphosphonates may cause renal toxicity. For patients with creatinine clearance

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Orthopedics <30-35 ml/min, use of parenteral bisphosphonates is not recommended. Other concerns are risk of kidney damage, osteonecrosis of jaw (Zoledronic acid), atypical fractures and atrial fibrillation.23-27 Selective estrogen receptor modulators Selective estrogen receptor modulators (SERMs) are nonsteroidal molecules that bind with high affinity to the estrogen receptor (ER) and act as agonists or antagonists depending on the target tissue. The ER agonist effects of SERMs in bone have proven to be important for the treatment of osteoporosis in postmenopausal women. Currently, raloxifene is the only SERM approved by the US Food and Drug Administration (FDA) for prevention and treatment of postmenopausal osteoporosis. Clinical studies have clearly demonstrated the efficacy of raloxifene in significantly reducing the risk of vertebral fracture. Raloxifene is indicated for the treatment and prevention of osteoporosis in postmenopausal women. The usual dose is 60 mg given orally daily. It can also be given in combination with calcium and vitamin D. Raloxifene is the first SERM studied for breast cancer prevention, and it decreases bone resorption through actions on ER. It has been shown to prevent bone loss, and data in females with osteoporosis have demonstrated that raloxifene causes a 35% reduction in the risk of vertebral fractures. It has also been shown to reduce the prevalence of invasive breast cancer. Prospective clinical trial data have not shown efficacy at nonvertebral and hip sites. An additional benefit and indication is prevention of ER-positive breast cancer.28-30 The limited antifracture efficacy of raloxifene has led to interest in developing other SERMs that might have a broader antifracture profile. Lasofoxifene, bazedoxifene and arzoxifene are new SERMs in late-stage treatment trials. RANK-Ligand inhibition: Denosumab Denosumab is a fully human monoclonal antibody that binds with high affinity and specificity to the RANKL, a key mediator of osteoclast formation, activity and survival. The inhibition of RANKL by denosumab reduces osteoclast-mediated bone resorption. It is indicated for the treatment of postmenopausal women with osteoporosis who are at high-risk of fracture (defined as a history of osteoporotic fracture), have multiple risk factors for fracture, are intolerant to other available osteoporosis therapies or in whom osteoporosis therapies have failed. In postmenopausal women with osteoporosis, denosumab reduces the incidence of vertebral, nonvertebral and hip fractures.

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Denosumab was approved by the US FDA in June 2010. Approved dosage is 60 mg given subcutaneously every six months. Several recent studies have demonstrated the efficacy of this new antiresorptive therapeutic class in terms of increasing BMD, decreasing bone turnover markers (BTMs) and most important, reducing fractures at vertebral, hip and other nonvertebral sites. Because RANKL is expressed in lymphocytes, safety concerns relate to inhibition of this important immunomodulator and to potential consequences such as infections. The clinical trials did not report an increased rate of serious infections related to denosumab, but there was a significantly increased incidence of eczema and hospitalization for cellulitis compared with placebo.31,32 Calcitonin Calcitonin is a hormone that decreases osteoclast activity, thereby impeding postmenopausal bone loss. It acts like the endogenous form of the hormone on the calcitonin receptor on osteoclasts to decrease their activity. Out of all recombinant or synthetic calcitonins that have been used for medical purposes, the salmon calcitonin preparation (SCT) is the most widely used. SCT as a nasal spray is the most commonly used calcitonin formulation due to its convenience of administration. It is recommended in conjunction with adequate calcium and vitamin D intake to prevent the progressive loss of bone mass. The intranasal spray is delivered as a single daily spray that provides 200 IU of the drug. The drug can be delivered subcutaneously, but this route is rarely used. It has reduced the incidence of vertebral fractures in women with pre-existing vertebral fractures. As a desirable additional effect, calcitonin has been noted to reduce the pain of clinical vertebral fractures. Calcitonin is an option for patients who are not candidates for other available osteoporosis treatments. Common side effects of nasally administered calcitonin include nasal discomfort, rhinitis, irritation of nasal mucosa and occasional epistaxis. Nausea, local inflammatory reactions at the injection site, sweating and flushing are side effects noted with parenteral use.33-35 Strontium ranelate Strontium ranelate, a novel orally active agent, has been developed for the treatment of osteoporosis. It consists of two atoms of strontium and an organic moiety ranelic acid. Strontium ranelate acts by both stimulating bone formation and decreasing bone resorption. In vitro, strontium ranelate has been shown to increase osteoblastic activity, including increasing

Orthopedics collagen synthesis and modulating the OPG/RANKL system in favor of OPG, as well as decrease bone resorption by decreasing osteoclast differentiation and resorbing activity and increasing osteoclast apoptosis. Strontium ranelate is approved for the treatment of osteoporosis in some countries in Europe. It reduces the risk of both spine and nonvertebral fractures. Strontium is not approved for the treatment of osteoporosis in the United States. Dose is 2 g sachet nightly taken at bedtime, mixed with >30 ml of water at least two hours after food. Strontium ranelate has rarely been associated with venous thromboembolism and severe hypersensitivity reactions, including Stevens-Johnson syndrome and drug rash with eosinophilia and systemic symptoms. Patients should be advised to seek immediate medical advice if they develop a rash.36-38 Teriparatide Teriparatide is a synthetic form of human parathyroid hormone, which acts by inhibiting bone resorption and increasing bone formation. Normally in response to low serum calcium, parathyroid hormone (PTH) is secreted from parathyroid glands, which acts to increase the concentration of calcium in serum by mobilizing calcium from bone. Pharmacologically, when PTH is administered intermittently at low doses, it has been shown to have predominantly anabolic effects on osteoblasts. PTH initiates bone formation first and only later promotes bone formation, which is indicated by bone turnover markers. Teriparatide is also indicated for use in men with a high-risk of fractures and where other treatments are unsuitable. Following a course of teriparatide it is recommended that patients use an antiresorptive medicine (e.g. a bisphosphonate) to further increase BMD and maintain the antifracture effect. Dose is 20 Îźg subcutaneous injection daily in the thigh or abdomen. Use is restricted to 18 month lifetime exposure (caused osteosarcoma in animal studies); informed consent is required. Transdermal teriparatide is also under development.39-41 Hormone replacement therapy Hormone replacement therapy (HRT) was once considered a first-line therapy for the prevention and treatment of osteoporosis in women. Although HRT is not currently recommended for the treatment of osteoporosis, it is important to mention because many osteoporosis patients in a typical practice still use it for controlling postmenopausal symptoms. Data from the Womenâ&#x20AC;&#x2122;s Health Initiative confirmed that HRT can reduce fractures. However, the results were distressing with respect to the adverse outcomes associated with combined estrogen and progesterone therapy

(e.g., risks for breast cancer, myocardial infarction, stroke and venous thromboembolic events) and estrogen alone (e.g., risks for stroke and venous thromboembolic events).42

Drugs Under Clinical Development Cathepsin K inhibitors Cathepsin K is critical for normal osteoclastic bone resorption. The two agents, which are under development are balicatib (AAE581) and odanacatib (MK-0822). Clinical trials with these agents have demonstrated increase in hip and lumbar spine BMD, with a significant reduction in bone resorption markers. A newer highly potent cathepsin K inhibitor named relacatib is presently being studied in experimental animals.43,44 Src kinase inhibitors Src kinase is a nonreceptor tyrosine kinase and a member of the Src family of protein kinases, which plays an important role in activity and survival of osteoclast cells. Osteopetrosis was caused in mouse due to Src inactivation, therefore it clearly indicated that Src is an important requirement for osteoclastic bone resorption. Saracatinib is a novel orally available competitive inhibitor of Src kinase shown to inhibit bone resorption in vitro. In a randomized, double-blind, placebo-controlled, multiple-ascending- dose Phase I trial, treatment with saracatinib inhibited osteoclastmediated bone resorption in healthy men without any significant adverse effects. The results of this study show that saracatinib has the potential to become an agent for the treatment of osteoporosis.45-47 New SERMs Lasofoxifene: Lasofoxifene is a nonsteroidal SERM under development for the prevention and treatment of osteoporosis and for the treatment of vaginal atrophy. In a dose of 0.5 mg/day, the dose that is intended for clinical use, it was associated with a reduction in the risk of ER-positive breast cancer, major coronary heart disease events and stroke, although the numbers of these events were small in all groups. Lasofoxifene was significantly associated with the risk of venous thromboembolic events and pulmonary embolism.48 Bazedoxifene: Bazedoxifene is a third-generation SERM under development for the prevention and treatment of postmenopausal osteoporosis. It is approved in the European Union (marketed in Italy and Spain) and is currently in the late phases of review by the US FDA. Bazedoxifeneâ&#x20AC;&#x2122;s combination with conjugated estrogens,

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Orthopedics Aprela, is currently undergoing Phase III studies for the treatment of postmenopausal symptoms (including the prevention of postmenopausal osteoporosis/treatment of osteopenia).49 Emerging therapy: The Wnt/β-catenin pathway regulates gene transcription of proteins important for osteoblast function. Study of the pathway has led to further discovery of inhibitors of Wnt signaling secreted by osteocytes. These include sclerostin and dickkopf1 protein (DKK1), both of which block binding of Wnt to LRP5 (lipoprotein receptor-like protein 5), thereby inhibiting osteoblast stimulation. Monoclonal antibodies designed to block the inhibiting action of both sclerostin and DKK1 are being considered for clinical trials based on promising results in animal models. Because both of these molecules appear to be secreted only by bone, it is hoped that they will have fewer systemic adverse effects. Therapies targeted at other molecules in the pathway, for example a small molecule inhibitor of GSK3β, the enzyme, which causes degradation of β-catenin in the absence of Wnt signaling, are considered less desirable targets due to their action in many tissues in addition to bone.50

Nonpharmacologic Management Although pharmacologic approaches represent the cornerstone of treatment, some patients cannot comply with medication regimens, particularly because of potential adverse effects, but also because some patients cannot afford certain medication options or are not willing to take medications for prolonged time periods. For such patients nonpharmacologic management may be helpful. ÂÂ

ÂÂ

848

Bracing:51 Bracing, or orthoses, such as thoracolumbar (mid to low back) braces are often prescribed for osteoporotic patients with vertebral compression fractures. Some braces are rigid and attempt to straighten the spine backward and are traditionally used in patients with an acute vertebral compression fracture. Fall prevention:52 Falls in the elderly represent a significant cause of morbidity and mortality. Fall prevention involves environmental modifications, medication review, exercise, gait assessment and treatment, provisions for assistive devices and attention to concomitant conditions resulting in unsteady gait. Environmental modifications can consist of minimizing clutter, altering slippery surfaces and providing grab bars and other supports in tubs and near toilets. Multiple medications can have a key role in falls. Medication review should, therefore, be performed

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on a regular basis, with unnecessary and potentially harmful medications eliminated. ÂÂ

Kyphoplasty:53 Kyphoplasty is a minimally invasive spine procedure that involves the infiltration of bone cement into a fractured vertebral body after fracture reduction using a balloon tamp. Indications for this procedure include relatively acute, painful compression fractures refractory to conservative treatment. Kyphoplasty can result in diminished pain and reduce kyphosis; multiple studies have shown it to be an effective treatment for painful compression fractures with sustained improvements in back pain, back function and quality-of-life.

References 1. Lirani-Galväo AP, Lazaretti-Castro M. Physical approach for prevention and treatment of osteoporosis. Arq Bras Endocrinol Metabol 2010;54(2):171-8. 2. Cooper C, Campion G, Melton LJ 3rd. Hip fractures in the elderly: a world-wide projection. Osteoporos Int 1992;2(6):285-9. 3. Kanis JA, Johnell O, De Laet C, Jonsson B, Oden A, Ogelsby AK. International variations in hip fracture probabilities: implications for risk assessment. J Bone Miner Res 2002;17(7):1237-44. 4. Malhotra N, Mithal A. Osteoporosis in Indians. Indian J Med Res 2008;127(3):263-8. 5. Mithal A, Dhingra V, Lau E; International Osteoporosis Foundation. The Asian Audit: epidemiology, costs and burden of osteoporosis in Asia 2009. IOP Publications, 2009. Available at http://www.iofbonehealth.org/asianaudit 6. World Health Organization. WHO scientific group on the assessment of osteoporosis at primary health care level: summary meeting report. Available at http://www.who. int/chp/topics/Osteoporosis.pdf. 7. Pande KC, Johansen KB, Helboe AB. Digital X-ray Radiogrammetry: Establishment and comparison of Indian Female and Male Normative Reference Data. J Bone Miner Res 2001;16:S456. 8. Raisz LG. Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J Clin Invest 2005;115(12):3318-25. 9. Seeman E, Delmas PD. Bone quality--the material and structural basis of bone strength and fragility. N Engl J Med 2006;354(21):2250-61. 10. Lindsay R, Cosman F. Osteoporosis. In: Harrison’s Principles of Internal Medicine. Faucy AS, Kasper DL, Longo DL, Hauser SL, Jameson JL, Loscajlo J, et al (Eds.), 18th edition, McGraw Hill Companies: New York 2012:p.3120-35. 11. Osteoporosis. In: Current Medical Diagnosis & Treatment. 51st edition, Mcphee SJ, Papadakis MA, Rabow

Orthopedics MW (Eds.), McGraw Hill Companies: New York 2012: p.1116-20. 12. NOF osteoporotic prevention- risk factors for osteoporosis. Available at http://www.nof.org/prevention/risk.htm. 13. Nikander R, Sievänen H, Heinonen A, Daly RM, Uusi-Rasi K, Kannus P. Targeted exercise against osteoporosis: A systematic review and meta-analysis for optimising bone strength throughout life. BMC Med 2010;8:47. 14. Peris P, Monegal A, Martínez MA, Moll C, Pons F, Guañabens N. Bone mineral density evolution in young premenopausal women with idiopathic osteoporosis. Clin Rheumatol 2007;26(6):958-61. 15. Watts NB, Bilezikian JP, Camacho PM, Greenspan SL, Harris ST, Hodgson SF, et al; AACE Osteoporosis Task Force. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract 2010;16 Suppl 3:1-37. 16. Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, Staehelin HB, Bazemore MG, Zee RY, et al. Effect of Vitamin D on falls: a meta-analysis. JAMA 2004;291(16):1999-2006. 17. Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, Arnaud S, et al. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med 1992;327(23):1637-42. 18. Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab 2011;96(1):53-8. 19. Prentice A. Diet, nutrition and the prevention of osteoporosis. Public Health Nutr 2004;7(1A):227-43. 20. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. January 2010. Available at http://www.nof.org/professionals/clinicalguidelines 21. Watts NB, Diab DL. Long-term use of bisphosphonates in osteoporosis. J Clin Endocrinol Metab 2010;95(4):1555-65. 22. Drake MT, Clarke BL, Khosla S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc 2008;83(9):1032-45. 23. Papapetrou PD. Bisphosphonate-associated events. Hormones (Athens) 2009;8(2):96-110.

adverse

24. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003;61(9):1115-7. 25. Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, et al; American Society for Bone and Mineral Research. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007;22(10): 1479-91.

26. Heckbert SR, Li G, Cummings SR, Smith NL, Psaty BM. Use of alendronate and risk of incident atrial fibrillation in women. Arch Intern Med 2008;168(8):826-31. 27. Sørensen HT, Christensen S, Mehnert F, Pedersen L, Chapurlat RD, Cummings SR, et al. Use of bisphosphonates among women and risk of atrial fibrillation and flutter: population based case-control study. BMJ 2008;336(7648):813-6. 28. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 1999;282(7):637-45. 29. Cauley JA, Norton L, Lippman ME, Eckert S, Krueger KA, Purdie DW, et al. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Multiple outcomes of raloxifene evaluation. Breast Cancer Res Treat 2001;65(2):125-34. 30. Barrett-Connor E, Grady D, Sashegyi A, Anderson PW, Cox DA, Hoszowski K, et al; MORE Investigators (Multiple Outcomes of Raloxifene Evaluation). Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA 2002;287(7):847-57. 31. Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, et al; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361(8):756-65. 32. Smith MR, Egerdie B, Hernández Toriz N, Feldman R, Tammela TL, Saad F, et al; Denosumab HALT Prostate Cancer Study Group. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 2009;361(8):745-55. 33. Overgaard K. Effect of intranasal salmon calcitonin therapy on bone mass and bone turnover in early postmenopausal women: a dose-response study. Calcif Tissue Int 1994;55(2):82-6. 34. Chesnut CH 3rd, Silverman S, Andriano K, Genant H, Gimona A, Harris S, et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. PROOF Study Group. Am J Med 2000;109(4):267-76. 35. Chesnut CH 3rd, Majumdar S, Newitt DC, Shields A, Van Pelt J, Laschansky E, et al. Effects of salmon calcitonin on trabecular microarchitecture as determined by magnetic resonance imaging: results from the QUEST study. J Bone Miner Res 2005;20(9):1548-61. 36. Reginster JY, Felsenberg D, Boonen S, Diez-Perez A, Rizzoli R, Brandi ML, et al. Effects of long-term strontium ranelate treatment on the risk of nonvertebral and vertebral fractures in postmenopausal osteoporosis:

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Orthopedics Results of a five-year, randomized, placebo-controlled trial. Arthritis Rheum.2008;58(6):1687-95. 37. Neuprez A, Hiligsmann M, Scholtissen S, Bruyere O, Reginster JY. Strontium ranelate: the first agent of a new therapeutic class in osteoporosis. Adv Ther 2008;25(12):1235-56. 38. Meunier PJ, Slosman DO, Delmas PD, Sebert JL, Brandi ML, Albanese C, et al. Strontium ranelate: dose-dependent effects in established postmenopausal vertebral osteoporosis - a 2-year randomized placebo controlled trial. J Clin Endocrinol Metab 2002;87(5):2060-6. 39. Deal C, Omizo M, Schwartz EN, Eriksen EF, Cantor P, Wang J, et al. Combination teriparatide and raloxifene therapy for postmenopausal osteoporosis: results from a 6-month double-blind placebo-controlled trial. J Bone Miner Res 2005;20(11):1905-11. 40. Finkelstein JS, Wyland JJ, Leder BZ, Burnett-Bowie SM, Lee H, Jüppner H, et al. Effects of teriparatide retreatment in osteoporotic men and women. J Clin Endocrinol Metab 2009;94(7):2495-501. 41. Gates BJ, Sonnett TE, Duvall CA, Dobbins EK. Review of osteoporosis pharmacotherapy for geriatric patients. Am J Geriatr Pharmacother 2009;7(6):293-323. 42. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al; Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002;288(3):321-33. 43. Zhao Q, Jia Y, Xiao Y. Cathepsin K: a therapeutic target for bone diseases. Biochem Biophys Res Commun 2009;380(4):721-3. 44. Podgorski I. Future of anticathepsin K drugs: dual therapy for skeletal disease and atherosclerosis? Future Med Chem 2009;1(1):21-34.

45. Hannon RA, Clack G, Rimmer M, Swaisland A, Lockton JA, Finkelman RD, et al. Effects of the Src kinase inhibitor saracatinib (AZD0530) on bone turnover in healthy men: a randomized, double-blind, placebo-controlled, multiple-ascending-dose phase I trial. J Bone Miner Res 2010;25(3):463-71. 46. Horne WC, Sanjay A, Bruzzaniti A, Baron R. The role(s) of Src kinase and Cbl proteins in the regulation of osteoclast differentiation and function. Immunol Rev 2005;208: 106-25. 47. Soriano P, Montgomery C, Geske R, Bradley A. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 1991;64(4):693-702. 48. Cummings SR, Ensrud K, Delmas PD, LaCroix AZ, Vukicevic S, Reid DM, et al; PEARL Study Investigators. Lasofoxifene in postmenopausal women with osteoporosis. N Engl J Med 2010;362(8):686-96. 49. Biskobing DM. Update on bazedoxifene: a novel selective estrogen receptor modulator. Clin Interv Aging 2007;2(3):299-303. 50. Baron R, Rawadi G. Targeting the Wnt/beta-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology 2007;148(6):2635-43. 51. Kaplan RS, Sinaki M. Posture Training Support: preliminary report on a series of patients with diminished symptomatic complications of osteoporosis. Mayo Clin Proc 1993;68(12):1171-6. 52. Sinaki M, Brey RH, Hughes CA, Larson DR, Kaufman KR. Significant reduction in risk of falls and back pain in osteoporotic-kyphotic women through a Spinal Proprioceptive Extension Exercise Dynamic (SPEED) program. Mayo Clin Proc 2005;80(7):849-55. 53. Lavelle WF, Cheney R. Recurrent fracture after vertebral kyphoplasty. Spine J 2006;6(5):488-93.

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Most Adults Ignore Fitness Recommendations Just over 20% of US adults get as much aerobic and muscle-strengthening exercise as recommended in government guidelines, CDC researchers said.

Weight Gain Common with New Knees Patients who undergo total knee replacement are at substantial risk for weight gain during the five years after the surgery, a large retrospective study showed.

Arthritis Setting into Increasingly Younger Knees Symptomatic knee osteoarthritis (OA) is now being diagnosed at relatively young ages, and almost one US adult in 10 will develop the disabling condition by age 60, researchers predicted. Source: Medpage Today

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Pulmonology

Pulmonary Alveolar Microlithiasis: A Clinicoradiological Dissociation Debaprasad Chakrabarti*, Prabhat Debbarma**, Amrit Kumar Bhattacharyyaâ&#x20AC;

Abstract Pulmonary alveolar microlithiasis (PAM) is a rare and slowly progressive disease characterized by widespread calcification within the alveoli with a paucity of symptoms in contrast to radiologic findings. We report here a case of pulmonary alveolar microlithiasis who presented to us with minimal chest complaints following chest trauma despite extensive imaging findings.

Keywords: Pulmonary alveolar microlithiasis

ulmonary alveolar microlithiasis (PAM) is an uncommon disease characterized by multiple microscopic calculi within the alveolar space in the absence of any known disorder of calcium metabolism.1-5 Symptoms related to PAM usually begin in the third or fourth decade and follow an autosomal recessive pattern.1,6 A hallmark of this disease is a striking dissociation between the radiological findings and the only mild clinical signs and symptoms. Pathogenesis of PAM is yet to be elucidated, though, recently mutation in the type-IIb sodium-phosphate cotransporter gene has been implicated.7 Case report A 27-year-old nonsmoker male presented to us with a history of mild chest pain following a history of blunt chest trauma sustained three months back. There was no history of cough, breathlessness, fever, joint pain or skin lesions. On physical examination, his blood pressure was 118/70 mmHg, pulse rate 68 bpm, respiratory rate 18 cycles/min without any clubbing, cyanosis or peripheral edema. Chest examination revealed bilateral symmetrical chest without deformity. On auscultation, there were very few scattered crackles at the bases. Rest of systemic examination was essentially normal.

were normal. Arterial blood gas analysis, echocardiography, pulmonary function tests (PFTs) and USG abdomen did not reveal any abnormality. As a part of routine test for chest trauma to find out the cause of chest pain, a chest radiograph was asked for, which showed diffuse micronodular calcification in both lungs, more pronounced in mid and lower zones (Fig. 1). A high-resolution computed tomography (HRCT) scan was then obtained, which revealed micronodular calcified opacities throughout both lungs (Figs. 2 and 3). Based on these clinicoradiological findings, a provisional diagnosis of PAM was considered and a lung biopsy was done, which showed round, concentrically laminated microliths in the alveoli confirming the diagnosis of PAM. The bronchoalveolar lavage fluid was negative for acid-fast bacilli (AFB) or fungi.

Investigations revealed normal complete blood count (CBC). His blood sugar, serum electrolytes, serum calcium, phosphorus and liver function tests *Associate Professor Dept. of Medicine, Tripura Medical College and Dr BRAM Teaching Hospital, Agartala **Assistant Professor Dept. of Radiodiagnosis, Agartala Govt. Medical College and GB Panth Hospital, Agartala â&#x20AC; Professor and Head Dept. of Medicine, Tripura Medical College and Dr BRAM Teaching Hospital, Agartala

Figure 1. Chest X-ray showing bilateral diffuse micronodular calcification (sandstorm-like).

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Pulmonology

Figure 2. HRCT chest showing septal thickening with bilateral multiple calcified nodules.

include ground glass opacity (most common), subpleural calcification, confluent and diffuse calcified nodules and dense consolidation. Septal thickening, ‘black pleura’ sign due to subpleural cyst and crazy paving pattern have also been described.7 But, imaging studies cannot confirm PAM in the absence of a histological diagnosis on transbronchial lung biopsy. Some findings of PAM like nodular calcification may be seen in tuberculosis, metastatic osteosarcoma, amyloidosis, silicoproteinosis, etc. Measurement of surfactant protein A (SP-A) and surfactant protein D (SP-D) can be considered as an alternative in monitoring disease activity.8 The prognosis is dismal with no effective treatment. Use of disodium etidronate in the treatment of PAM is associated with mixed results. Lung transplantation is the only hope for end-stage PAM. Conclusion Our patient had all the clinical, radiological and histological findings, which make PAM a secure diagnosis. The case is presented because of its rarity. The striking dissociation between the frightening imaging findings and virtually asymptomatic status of the individual will sensitize the clinicians to consider PAM in every such patient to avoid misdiagnosis. References

Figure 3. HRCT thorax showing subpleural calcification and calcification along interlobar septa.

1. Barbolini G, Rossi G, Bisetti A. Pulmonary alveolar microlithiasis. N Engl J Med 2002;347(1):69-70.

Discussion

2. Cluzel P, Grenier P, Bernadac P, Laurent F, Picard JD. Pulmonary alveolar microlithiasis: CT findings. J Comput Assist Tomogr 1991;15(6):938-42.

PAM is an uncommon disease characterized by numerous small calculi in alveolar spaces with a chronic and deteriorating evolution.1 Patients may be asymptomatic for many years and usually become symptomatic between third and fourth decades.2,3 Clinical presentation includes cough, breathlessness and chest pain and a lung disorder with restrictive pattern.3,7 Adult patients show a slowly progressive downhill course with decline in lung function, resulting in respiratory failure and cor pulmonale. Death can occur in midlife. It is an autosomal recessive disease; the etiopathogenesis is still unclear. The role of mutation in type-IIb sodium-phosphate cotransporter gene (SCL34A2 gene) present on chromosome4, which regulates phosphate homeostasis in various organs including lung has been recently implicated.7 Plain chest x-ray usually shows diffuse bilateral symmetric micronodular calcification (sandstorm) mainly in middle and lower zones; apical bullae and black pleural lines.5 HRCT thorax remains the imaging technique of choice to diagnose PAM. The findings

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3. Hoshino H, Koba H, Inomata S, Kurokawa K, Morita Y, Yoshida K, et al. Pulmonary alveolar microlithiasis: highresolution CT and MR findings. J Comput Assist Tomogr 1998;22(2):245-8. 4. Marchiori E, Gonçalves CM, Escuissato DL, Teixeira KI, Rodrigues R, Barreto MM, et al. Pulmonary alveolar microlithiasis: high-resolution computed tomography findings in 10 patients. J Bras Pneumol 2007;33(5):552-7. 5. Korn MA, Schurawitzki H, Klepetko W, Burghuber OC. Pulmonary alveolar microlithiasis: findings on highresolution CT. AJR Am J Roentgenol 1992;158(5):981-2. 6. Castellana G, Gentile M, Castellana R, Fiorente P, Lamorgese V. Pulmonary alveolar microlithiasis: clinical features, evolution of phenotype, and review of the literature. Am J Med Genet 2002;111(2):220-4. 7. Huqun, Izumi S, Miyazawa H, Ishii K, Uchiyama B, Ishida T, et al. Mutations in the SLC34A2 gene are associated with pulmonary alveolar microlithiasis. Am J Respir Crit Care Med 2007;175(3):263-8. 8. Gasparetto EL, Tazoniero P, Escuissato DL, Marchiori E, Frare E Silva RL, Sakamoto D. Pulmonary alveolar microlithiasis presenting with crazy-paving pattern on high resolution CT. Br J Radiol 2004;77(923):974-6.

Pediatrics

Amniotic Fluid Lamellar Body Count as a Predictor of Fetal Lung Maturity Sunanda Kulkarni*, Jayamma*

Abstract Assessment of fetal lung maturity can be done with various biochemical tests on amniotic fluid. In the present study, lamellar body count (LBC) was compared with the traditional shake bubble test (SBT), as LBC is a simple, reliable and cost-effective method to predict fetal lung maturity. This was a prospective study conducted on 50 patients with known last menstrual period (LMP), gestational age >28 weeks presenting in active phase of labor with intact membranes. Amniotic fluid was collected either through vaginal route or through amniocentesis and SBT and LBC were conducted on all samples. Newborns were watched for signs of respiratory distress syndrome (RDS). Fourteen babies developed RDS. i.e., one out of 34 babies with positive SBT, seven out of 10 with intermediate SBT, all six with negative SBT developed RDS. The LBC varied between 3,000-28,000/ml among the 14 babies with RDS. i.e., all cases with RDS had LBC <30,000/ml. This study showed that LBC with cut-off value of 30,000/ml to predict fetal lung maturity is superior to all other tests in terms of technique and cost-effectiveness.

Keywords: Lamellar body count, shake bubble test, amniocentesis, respiratory distress syndrome

espiratory distress syndrome (RDS) due to prematurity is the leading cause of perinatal morbidity and mortality in obstetric practice. It is important to predict fetal lung maturity accurately with a quick cost-effective method before termination of pregnancy, particularly in problem pregnancies such as previous lower-segment cesarean section (LSCS), precious pregnancy requiring interventions for associated risks and those pregnancies with unreliable dates, irregular cycles, etc. It is well-known that in pathological cases fetal lung maturity deviates from that which occurs in normal pregnancy thereby further complicating the decision for termination. Various biochemical tests done on amniotic fluid can assess fetal lung maturity. It includes lecithin/ sphingomyelin (L:S) ratio, detection of phosphatidyl glycerol, dipalmitoyl phosphatidylcholine estimation, Shake bubble test (SBT), fluorescence polarization, optical density at 650 nm and lamellar body count (LBC). L:S ratio is the time honored standard test for assessing fetal lung maturity, but it is expensive, laborious and time consuming. SBT is a rapid, inexpensive bedside test, but it is inconclusive when test results are intermediate.

*Dept. of Obstetrics and Gynecology Bowring & Lady Curzon Hospital Bangalore Medical College, Bangalore

Lamellar bodies are storage forms of surfactant released by type 2 pneumocytes in the amniotic fluid. As they have the same size as platelets, they can be easily quantified using automated hematological cell counts, set for platelet quantification. Their production starts at 20-24 weeks of gestational age and are released into lung fluid at a basal rate. Secretion is stimulated by labor and initiation of air breathing. Aim As LBC is an inexpensive test this study was done to evaluate its reliability as a possible cost-effective alternative in assessing the fetal lung maturity. Material and Methods The study was conducted on 50 patients with known last menstrual period (LMP), gestational age >28 weeks and who delivered within 72 hours of collection of amniotic fluid. This included women reporting in active phase of labor with intact membranes, women presenting with threatened preterm labor, women with severe pregnancy-induced hypertension (PIH) or intrauterine growth restriction (IUGR) who need induction. Women with hydramnios, oligohydramnios, multiple pregnancy, anemia, heart disease, antepartum hemorrhage, chorioamnionitis, intrauterine death (IUD) and those in whom the amniotic fluid was grossly contaminated with blood, meconium and mucus were excluded from the study.

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Pediatrics Samples were collected through vaginal route in those who come in active phase of labor with intact bag of membranes, using Sims speculum and sterile 10 cc syringes. Whenever amniotic fluid could not be collected from the bag of membranes, vaginal pool of liquor was aspirated. Samples were collected by amniocentesis in one case of severe PIH and two cases of threatened preterm labor. In one case, amniotic fluid was collected during cesarean section. Samples of amniotic fluid were tested within 4-6 hours of collection or preserved at 4°C until they were taken for testing. SBT was done immediately after collection using uncentrifuged samples. LBC was done using automated hematological cell counter. RDS was diagnosed in the newborn when all the following criteria were present. ÂÂ

Physical signs such as nasal flaring, grunting, cyanosis and tachypnea.

ÂÂ

Supplementary oxygen requirement for >24 hours.

ÂÂ

Radiographic opacities.

findings

widespread

lung

Results The study group of 50 patients was constituted by 29 (58%) term pregnancies, eight (16%) preterm normal pregnancies, seven (14%) PIH cases and six (12%) PIH cases with preterm pregnancies. From Table 1, it is seen that SBT was positive in 34 cases; of which, one baby developed RDS; intermediate in 10 cases out of which seven babies developed RDS and negative in six cases, where all babies developed RDS. Same Table shows that all 13 cases with gestational age <34 weeks developed RDS, while only one out of 37 cases with gestational age >34 weeks-developed RDS. Also, RDS developed in all six babies weighing <1.5 kg and eight out of 44 babies weighing >1.5 kg. Among 50 cases, LBC was <30,000/µl in 15 cases between 30,000-35,000/µl in five cases and >35,000/µl in 30 cases. Those who developed RDS had LBC between 3,000-28,000/µl. Sensitivity and specificity of LBC to predict RDS with cut-off values of 30,000/µl and 35,000/µl are shown in Table 2.

Those cases classified as transient tachypnea of newborn were also considered as RDS.

Since LBC <30,000/µl is more specific than 35,000/µl in predicting RDS, a cut-off of <30,000/µl is taken.

For both tests (SBT and LBC), sensitivity, specificity, positive and negative predictive values were calculated.

Discussion

Table 1. SBT, Maturity and Birth Weight in Relation to RDS No. of cases

RDS absent

RDS present

Positive

Intermediate

Negative

Total

Shake bubble test

New born maturity Below 34 weeks

Above 34 weeks

Total

Birth weight Below 1.5 kg

Above 1.5 kg

Total

From the present study, we found that all the 14 babies with RDS had LBC <30,000/µl. Only 13 babies with RDS showed negative SBT (negative and intermediate results are taken as negative). On comparing sensitivity, specificity and predictive values of SBT and LBC, we found that LBC is more sensitive, more specific and has better predictive value than SBT in predicting RDS (Table 3). Comparison of methodology of SBT and LBC showed that LBC is a simple, inexpensive, rapid test and requires only small quantity of amniotic fluid. Contamination does not interfere with test results and no special training is needed to conduct the test (Table 4). Cacyea and co-workers have claimed that at term fetal lung is more echogenic than liver. However, as the perception of echogenicity is subjective, this aspect needs further work up. To date, various biochemical tests on amniotic fluid continue to be the standard

Table 2. Clinical Utility of LBC at Various Cut-off Levels LBC

P value

Sensitivity

Specificity

Positive PV

Negative PV

<30,000/µl

<0.001

100%

97.2%

93.3%

100%

<35,000/µl

<0.0001

100%

86.1%

73.6%

100%

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Pediatrics studies 35,000/ml according to Mittal et al, Ashwood et al; 26,000/ml according to Dubin et al and 37,000/ml according to De Roche study. All have used different centrifugation protocols. J Matern Fetal Neonatal Med quotes, “optimal L:S ratio of >3 and LBC of >50,000/ml for predicting lung maturity in diabetic women and 30,000/ml in nondiabetic.”

Table 3. Sensitivity and specificity of SBT and LBC Parameters in Sensitivity Specificity Positive Negative PV PV amniotic fluid SBT

92.8%

91.6%

81.2%

97%

LBC

100%

97.2%

93.3%

100%

PV = Predictive value.

As suggested by Nerhoff 2003, LBC procedure, sample preparation, equipment need standardization to find uniform threshold values where RDS are not seen.

Table 4. Comparison of Methodology of LBC and SBT LBC

SBT

Simplicity

Methodology

Simple

Duration

5 min

15 min

Quantity of amniotic fluid required

0.4 ml

2.25 ml

Observer bias

Absent

Present

Readily accessible

Specialized training

Not required

Cost

Inexpensive

Feasible

Not feasible

Accessibility

Meconium/Blood contamination

Conclusion From the present study, we found that LBC cut-off of 30,000/ml is optimum for predicting RDS. LBC is equal to SBT in simplicity and cost-effectiveness and superior to SBT in reliability. Suggested Reading 1. Ashwood ER, Oldroyd RG, Palmer SE. Measuring the number of lamellar body particles in amniotic fluid. Obstet Gynecol 1990;75(2):289-92.

tests to measure surfactant and hence predict fetal lung maturity. Rapidness, reliability, feasibility and costeffectiveness are of concern in applying these tests. Studies by Ashwood et al, Mittal et al and Dalence et al have inferred LBC to be a rapid, reliable, feasible and cost-effective test for fetal lung maturity. In a study by DeRoche et al, LBC was found to be a reliable test in pregnancies complicated by diabetes mellitus. Though Ashwood et al from their study opined that LBC should not be carried out on contaminated vaginal pool sample, Dubin and Dalence et al showed that contamination did not affect LBC significantly. Our present study also found the same. The recommended cut-off value for LBC is 30,000/ml according to Dalence et al, Fakhoury, Dowie et al;

2. Dalence CR, Bowie LJ, Dohnal JC, Farrell EE, Neerhof MG. Amniotic fluid lamellar body count: a rapid and reliable fetal lung maturity test. Obstet Gynecol 1995;86(2):235-9. 3. Dubin SB. Characterization of amniotic fluid lamellar bodies by resistive-pulse counting: relationship to measures of fetal lung maturity. Clin Chem 1989;35(4):612-6. 4. Fakhoury G, Daikoku NH, Benser J, Dubin NH. Lamellar body concentrations and the prediction of fetal pulmonary maturity. Am J Obstet Gynecol 1994;170(1 Pt 1):72-6. 5. DeRoche ME, Ingardia CJ, Guerette PJ, Wu AH, LaSala CA, Mandavilli SR. The use of lamellar body counts to predict fetal lung maturity in pregnancies complicated by diabetes mellitus. Am J Obstet Gynecol 2002;187(4): 908-12. 6. Ghidini A, Spong CY, Goodwin K, Pezzullo JC. Optimal thresholds of the lecithin/sphingomyelin ratio and lamellar body count for the prediction of the presence of phosphatidyl glycerol in diabetic women. J Matern Fetal Neonatal Med 2002;12(2):95-8.

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New Guide for Electrophysiology Training in Peds The Pediatric and Congenital Electrophysiology Society (PACES) has laid out what needs to be included in advanced fellowship programs for the field. Among the recommendations is that all fellows must receive training in device implantation because of “the increasing importance of resynchronization therapy and antitachycardia devices in modern cardiac care,” according to the PACES training and credentialing committee chaired by Edward Walsh, MD, of Boston Children’s Hospital. (Source: Medpage Today)

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Radiology

Ruptured Pulmonary Hydatid Cyst: The Camalote Sign Manjot Kaur*, Rakendra Singh**

Abstract Echinococcosis or hydatid disease is caused by larvae of the tapeworm Echinococcus. It remains an important health problem, especially in regions with inadequate hygienic environments and poor veterinarian control. Liver is the most common organ of involvement in adults and lungs are commonly involved in younger people. The cysts are characteristically seen as solitary or multiple circumscribed or oval masses on imaging. The characteristic imaging appearance changes with rupture of cyst. Surgery is the recommended form of treatment. We present a case of ruptured pulmonary hydatid cyst with communicating rupture into the bronchus, which is not very common.

Keywords: Hydatid cyst, rupture, computed tomography

he vast majority of infestations in humans are caused by Echinococcus granulosus. It causes cystic echinococcosis, which has a worldwide distribution.1 Humans are exposed less frequently to E. multilocularis, which causes alveolar echinococcosis. The hydatid tapeworm (E. granulosus) requires two hosts to complete its life cycle. Dogs (and other canines) are the definitive hosts and a variety of species of warm-blooded vertebrates (sheep, cattle, goats, horses, pigs, camels and humans) are the intermediate hosts. Humans are accidental hosts and do not play a role in the biological cycle. As two mammalian species are required for completion of the life cycle, direct transmission of echinococcosis from human-to-human does not occur. Case report A 70-year-old male came to the Dept. of Medicine of our hospital with complaints of dyspnea, productive cough and pain chest following a mild chest trauma. He mentioned that his expectoration was salty in taste. On general examination, patient was hemodynamically stable and had mild respiratory distress. Patient was afebrile and had no cyanosis

or pallor. A previous computed tomography (CT) scan done about a month back at outside multislice scanner, showed a well-defined cystic lesion measuring 10.1 x 7.2 cm in size in posterior basal segment of left lower lobe (Fig. 1) and provisional diagnosis of intrapulmonary hydatid cyst was given. On presentation at our institute a CT scan was planned. CT scanning of the lungs with CT/e scanner (GE; Milwaukee, USA) using 130 mA, 120 kV, 7-s scan time, 512 Ă&#x2014; 512 matrix, and 7 mm section thickness was done. Anteroposterior (AP) scout film from CT showed a well-defined oval cavitating lesion with air-fluid level in the lower zone of left lung abutting the left dome of diaphragm (Fig. 2). On CT axial sections, a large spherical air-filled cavity with collapsed membranes was seen in the posterior basal segment of left lung (Figs. 3 and 4). Surrounding consolidation was seen. Left pleural effusion was noted. Well-defined cysts were also seen in the liver and gastrophrenic ligmanent on CT (Fig. 5). Diagnosis of findings suggestive of pulmonary hydatid cyst with communicating rupture into bronchus was given. The Casoni and indirect hemagglutination tests were found to be positive. Diagnosis was confirmed at surgery. Discussion

*Assistant Professor, Dept. of Radiodiagnosis **Assistant Professor Dept. of Internal Medicine Adesh Institute of Medical Sciences and Research, Bathinda, Punjab Address for correspondence Dr Manjot Kaur 118/1, Gurjaipal Nagar, Jalandhar - 144 001, Punjab E-mail: drmanjot@hotmail.com

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Hydatid disease is one of the most important helminthic diseases. The lung is the second most common involved organ, but in children it is the commonest site. The lung may be affected when the liver is bypassed via the lymphatic system.2 Pulmonary hydatid cyst may rupture into pleural cavity, pericardium or the bronchial tree leading to cough, chest pain and hemoptysis.

Radiology

Figure 1. Axial CT of chest (mediastinal window) showing well-defined cystic lesion in the posterior basal segment of left lung lower lobe.

Figure 4. Axial CT of chest (mediastinal window) shows a cystic lung lesion (HC) with dependent wavy contour consistent with germinative membranes (GM) - the camalote or the water lily sign. Minimal left pleural effusion seen.

Figure 2. CT scout film showing a cavitating lesion in the left lower zone abutting the left dome of diaphragm.

Figure 5. Axial CT of upper abdomen showing a welldefined cystic lesion in the gastrophrenic ligament proven to be hydatid cyst at surgery.

The patients define this as a salty or peppery water expectoration, indicating spring-water expectoration, and it may even be an expectoration of membrane particles.3

Figure 3. Axial CT of chest (lung window) shows spherical cystic lesion (HC) with air-fluid level and surrounding consolidation in the posterior basal segment of left lung lower lobe.

The most frequent complication of pulmonary hydatid disease is the rupture of the cyst into a bronchus, which is also regarded as a complicated cyst.4 The rupture of echinococcal cysts is of three types: Contained, communicating and direct. Contained rupture occurs when only the parasitic endocyst ruptures and the cyst contents are confined within the host-derived pericyst. When cyst contents escape via bronchial or biliary radicles that are incorporated in the pericyst, the rupture is communicating. Direct rupture occurs when both the endocyst and the pericyst tear, spilling cyst contents directly into the peritoneal or

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Radiology pleural cavities or occasionally into other structures. Communicating and direct forms have more serious clinical implications than contained rupture, but even contained rupture needs prompt surgical attention to prevent it from developing into one of the other forms.5 In our case, a cavity with air-fluid level and collapsed germinative layers consistent with direct rupture of hydatid cyst into left lower bronchus was seen. Surrounding consolidation and mild pleural effusion was likely due to inflammatory response to endobronchial spread of cyst contents as no larvae or membranes could be elucidated in the pleural fluid. Conventional chest radiography has been the mainstay investigation for diagnosis of hydatid disease of the lungs, often coupled with Casoni skin testing and serologic testing for antibodies. A variety of descriptive have been given to plain film findings if rupture of cyst occurs with the air around or within the endocyst, an air-fluid level and the collapsed, crumpled membranes floating in the fluid. The ‘camalote or water lily’ sign is described when endocyst membrane float on top of remaining fluid due on collapse of endocyst and partial evacuation of fluid. This was demonstrated in our case. The other signs named are the 'meniscus/crescent’ sign, the sign of the ‘rising sun’, the ‘serpent’ sign, the ‘whirl’ sign, the ‘onion peel’ sign and the ‘cumbo’ sign.6-8 Sometimes, after rupture of a cyst into the bronchus, an inflammatory reaction may close the draining bronchus and imprison the membrane (incarcerated membrane). In these cases, the definite regular outline is lost and there may be a blurred shadow that can easily be mistaken for tuberculous focus or carcinoma (Ivanissevich sign).3 CT scan is useful to confirm the diagnosis and it is also able to demonstrate cysts not identified with plain radiographs.8 Apart from the classically described features of pulmonary hydatid disease, a crescentshaped rim of air at the lower end of the cyst (inverse

crescent sign) and a bleb of air in the wall of as-yet unruptured cysts (signet ring sign) have also been described on CT scan.9 Conclusion CT scan helps to elucidate the cystic nature of the lung mass, its accurate localization and evidence of any form of rupture so that surgical treatment can be planned at the first opportunity to avoid potentially fatal complications. References 1. Kurt Y, Sücüllü I, Filiz AI, Urhan M, Akin ML. Pulmonary echinococcosis mimicking multiple lung metastasis of breast cancer: the role of fluoro-deoxy-glucose positron emission tomography. World J Surg Oncol 2008;6:7. 2. Rebhandl W, Turnbull J, Felberbauer FX, Tasci E, Puig S, Auer H, et al. Pulmonary echinococcosis (hydatidosis) in children: results of surgical treatment. Pediatr Pulmonol 1999;27(5):336-40. 3. Xanthakis D, Efthimiadis M, Papadakis G, Primikirios N, Chassapakis G, Roussaki A, et al. Hydatid disease of the chest Report of 91 patients surgically treated. Thorax 1972;27(5): 517-28. 4. Doğan R, Yüksel M, Cetin G, Süzer K, Alp M, Kaya S, et al. Surgical treatment of hydatid cysts of the lung: report on 1055 patients. Thorax 1989;44(3):192-9. 5. Lewall DB, McCorkell SJ. Rupture of echinococcal cysts: diagnosis, classification, and clinical implications. AJR Am J Roentgenol 1986;146(2):391-4. 6. Pedrosa I, Saíz A, Arrazola J, Ferreirós J, Pedrosa CS. Hydatid disease: radiologic and pathologic features and complications. Radiographics 2000;20(3):795-817. 7. Haliloglu M, Saatci I, Akhan O, Ozmen MN, Besim A. Spectrum of imaging findings in pediatric hydatid disease. AJR Am J Roentgenol 1997;169(6):1627-31. 8. Celik M, Senol C, Keles M, Halezeroglu S, Urek S, Haciibrahimoglu G, et al. Surgical treatment of pulmonary hydatid disease in children: report of 122 cases. J Pediatr Surg 2000;35(12):1710-3. 9. Koul PA, Koul AN, Wahid A, Mir FA. CT in pulmonary hydatid disease: unusual appearances. Chest 2000;118(6):1645-7.

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Surgery

Gastric Rupture Following Blunt Trauma Abdomen: A Case Report Ritesh Maheshwari*, Ashutosh Sayana**, Pankaj Mahesh†

Abstract Blunt trauma abdomen is a common sequel to road traffic accident. The variety of intra-abdominal injuries following blunt trauma abdomen is diverse. We report a stomach laceration following a trivial trauma to abdomen in a otherwise healthy young male.

Keywords: Blunt trauma abdomen, road traffic accident, intra-abdominal injuries

lobally, injury accounts for 10% of all deaths. It is estimated that by 2020, 8.4 million people will die per year from injury. Injuries from traffic collisions will be the third most common cause of disability worldwide and second most common cause in the developing world.1 Blunt trauma abdomen is a common sequel to road traffic accidents and may cause various types of injuries ranging from solid organs to hollow viscera. We report a case of gastric rupture, which occurred following trivial trauma to abdomen. CASE REPORT A 20-year-old male, laborer by occupation, presented with pain and progressive distention of abdomen, hematemesis (1 episode) following cycle handle bar injury on collision with scooter about six hours prior to presentation. Patient was conscious, well oriented to time, place and person. He had tachycardia with systolic blood pressure (BP) of 90 mmHg and Glasgow coma scale of 15. There were no apparent external injuries except a small bruise in epigastrium. Abdomen was tense and tender with obliteration of liver dullness and absent bowel sounds. Patient was initially stabilized and chest X-ray revealed gas under diaphragm; sonography showed free fluid

Figure 1. Full thickness stomach laceration seen on laparotomy.

Grading of Gastric Injuries Grade I

Hematoma Contusion/Hematoma without devascularization Laceration Partial thickness

Laceration <2 cm in GE junction/pylorus <5 cm in proximal one-third

*Senior Resident **Associate Professor Dept. of Surgery, Government Medical College, Haldwani, Uttaranchal †Consultant Radiologist Parakh Imaging Centre, Haldwani, Uttaranchal Address for correspondence Dr Ritesh Maheshwari Senior Resident, Dept. of Surgery, Government Medical College Rampur Road Haldwani, Uttaranchal E-mail: rsm1819@rediffmail.com

<10 cm in distal two-third III

Laceration >2 cm in GE junction/pylorus ≥5 cm in proximal one-third ≥10 cm in distal two-third

IV Vascular

Tissue loss/Devascularization ≤two-third stomach

Vascular

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Surgery with internal echoes. Patient was taken up for laparotomy and was found to have serosanguinous and bilious fluid with undigested food particles, full thickness stomach laceration approximately 4 cm proximal to pylorus involving nearly two-third of circumference and small hematoma of transverse mesocolon. Distal gastrectomy with double layer closure of duodenal stump with anastomosis of proximal stump to jejunum (end to side) was done. Hematoma of transverse mesocolon required no intervention. Postoperatively patient progressed well and was discharged on 10th postoperative day. Histopathologic study of the resected specimen revealed few neutrophilic infiltrates suggestive of acute inflammation. DISCUSSION Blunt abdominal trauma usually results from motor vehicle collisions, assaults, recreational accidents or falls. The most commonly injured organs are the spleen, liver, retroperitoneum, small bowel, kidneys, bladder, colorectum, diaphragm and pancreas. Physical examination findings are notoriously unreliable for several reasons; few examples are the presence of distracting injuries, an altered mental state and drug and alcohol intoxication in the patient. Men tend to be affected slightly more often than women. Blunt force injuries to the abdomen can generally be explained by three mechanisms. The first is when rapid deceleration causes differential movement among adjacent structures. As a result, shear forces are created and cause hollow, solid, visceral organs and vascular pedicles to tear, especially at relatively fixed points of attachment. The second is when intra-abdominal contents are crushed between the anterior abdominal wall and the vertebral column or posterior thoracic cage. This produces a crushing effect, to which solid viscera (e.g., spleen, liver, kidneys) are especially vulnerable. The third is external compression forces that result in a sudden and dramatic rise in intra-abdominal pressure and culminate in rupture of a hollow viscous organ. Isolated gastric injury in blunt trauma abdomen is rarest of rare injury. The rarity of gastric rupture from blunt trauma is thought to be related to the stomachâ&#x20AC;&#x2122;s relatively protected anatomical position, high-degree of mobility, thick muscular wall and usual state of relative emptiness.2 When the stomach is distended, as by a recent meal, blunt trauma to the upper abdomen can lead to an increase in

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intragastric pressure sufficient to cause rupture. A history of a recent meal prior to gastric rupture is a common theme related to this injury; this signifies the importance of gastric distension as a predisposing factor to rupture. Blunt gastric rupture can occur in any portion of the stomach. It usually occurs as a single lesion, which is commonly debrided and repaired by primary closure. The site most commonly affected is the anterior wall (40%), followed by the greater curvature (23%), the lesser curvature (15%) and the posterior wall (15%). In our review of the literature, only two other cases have been reported where a patient was found to have sustained two separate gastric perforations from blunt trauma.3Â Furthermore, to our knowledge, there has been no reported case of a patient requiring a partial gastrectomy because of the extent of the gastric damage. Although patient had a full stomach prior to the injury, the patient was not found to have any predisposing weakness of the gastric wall that may be seen with ulcer disease, gastric cancer or previous gastric surgery. Associated injuries are frequently seen in cases of gastric rupture. Splenic injury is generally the most common associated injury; thoracic injury is the second most common. The majority of complications related to gastric rupture are septic in nature.4Â The mortality associated with gastric rupture has been reported to range from 0 to 66%.2-6 References 1. Murray CJ, Lopez AD. Regional patterns of disabilityfree life expectancy and disability-adjusted life expectancy: global Burden of Disease Study. Lancet 1997;349(9062):1347-52. 2. Yajko RD, Seydel F, Trimble C. Rupture of the stomach from blunt abdominal trauma. J Trauma 1975;15(3): 177-83. 3. Semel L, Frittelli G. Gastric rupture from blunt abdominal trauma. N Y State J Med 1981;81(6):938-9. 4. Brunsting LA, Morton JH. Gastric rupture from blunt abdominal trauma. J Trauma 1987;27(8):887-91. 5. Courcy PA, Soderstrom C, Brotman S. Gastric rupture from blunt trauma. A plea for minimal diagnostics and early surgery. Am Surg 1984;50(8):424-7. 6. Richardson G, Schiller WR, Shuck J. Gastric rupture from blunt trauma. Rocky Mt Med J 1979;76(6):309-10.

Medifinance

Need for a Will or Power of Attorney

ill a personâ&#x20AC;&#x2122;s family know what to do when one dies? Will all the members affected know how to respond if one becomes disabled? Is a person prepared to deal with a disability-related early retirement? If not, it will not be the plans that fail. The problem will be the failure to plan! Common Pitfalls Every family, every year, should be sure to train itself to be prepared for the worst of circumstances. Yet, most people do not bother to take the essential measures. Many do not have adequate amounts of life insurance. Others neglect their wills. Many people with complex needs have only a simplistic will when a carefully drawn trust is really needed. Some haphazardly purchase financial products and have no overall financial plan. Every estate is planned, either actively or passively. Either you maintain control, or the government does it for you. If one does not bother, his family may suffer undue duress and expense due to protracted court proceedings. You can avoid all this by planning ahead. Reasons to Plan In the case of a minor child or elderly parent. For example; one would not think of leaving them alone without a baby sitter. Nor would one allow someone else to decide who that baby sitter should be. It is important for a doctor to specify a guardian (and alternate guardians) in his will. A doctorâ&#x20AC;&#x2122;s spouse or family members cannot be expected to know all his financial arrangements. He can save them a lot of anguish by keeping records current, including bank account numbers, insurance policies, real estate deeds and records, stocks, bonds and other investments, wills, trust agreements, employee benefit records, birth certificates, marriage license, military service records and Social Security information. Employee benefit accounts and beneficiary arrangements change frequently, and often it is appropriate to change prior elections.

It is essential for a doctor to keep an inventory of all his property, mortgage information and an informal letter of instructions regarding estate administration. It is also important for the doctor to make sure he is doing everything possible to assure adequate income at retirement. He should take full advantage of savings, investments, insurance, individual retirement accounts and all the products and services available to him. His professional financial advisor must help him understand the advantages and disadvantages of each. Special Arrangements may be Needed A doctor owes it to himself and his loved ones to become informed, and to teach his survivors now, how to make decisions and handle money. Maintaining oneâ&#x20AC;&#x2122;s financial safety often means that, if a doctor is not well, he or his wife may not be able to handle money, run a business or manage an investment portfolio. It would be unfair and unwise to thrust these burdens on the wrong people. If a doctor has a mentally challenged, learning disabled or physically handicapped child, he must plan ahead. Such children may never be able to care for themselves. The same might apply to a parent or dependent sibling. Such cases call for special legal arrangements, and frequently require special funding efforts to be effective. Every closely held business owner should consider what will happen if a business associate dies or becomes disabled. What will happen to his survivors if he meets with an accident? Could his spouse or children take over if they had to? Would he want them to? If there are no written, binding plans, could the wrong employees take control? Suppose he is single. Who will act for him later, if he does not act for himself now? A doctor may have important charitable objectives. Government cutbacks have shifted some responsibility for social services back to the public, and many worthwhile organizations have a great need for funds. He may be contributing time and money now - what about a legacy after his death?

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Medifinance personal disability coverage waivers of premium.

Benefits of Planning Controlled estate planning will systematically uncover problems and gaps in his estate and provide solutions. For example, he can plan against: ÂÂ

Excessive transfer costs: The improper plan or group of documents might cause too much tax, payable too soon.

ÂÂ

Lack of liquidity: Or not enough cash to pay taxes and other predictable expenses could result in the forced sale of his liquid assets or other income producing property. This is an especially critical factor for owners of closely held businesses or investment real estate.

ÂÂ

Improper disposition of assets: This could result in the estate being disposed of in equal but inequitable shares among his children, even if their needs vary greatly. It may also be an improper disposition of assets to leave forty or fifty lakhs in life insurance to a 21-year-old child or to a spouse - without the benefit of a trust arrangements to prioritize for proper investment or to preclude wild spending. Inadequate income if disability occurs: Electing the maximum benefits from his employersponsored plans, and filling in the gaps with

ÂÂ

and

insurance

Inadequate income for his family at his death: To maintain the same standard of living, the family will typically need 80% of his present gross income. This must be adjusted periodically for inflation, additional debts incurred, education funding needs and special family circumstances.

How to Proceed Consult with a professional financial advisor to check all his insurance. Review his will and trust, making sure these documents will do, what he wants them to do in the most effective manner? Inform his heirs, before they become heirs, where his personal and financial documents are located especially a durable power of attorney. If he is married, he should measure his needs annually, establish his priorities and then develop and put into effect plans to make sure that his financial future is sound. It is not necessary to cancel and entirely redraw his legal instrument. A will can be modified by a codicil (amendment), and some forms of trust agreements are also subject to alteration. Of course, his attorney will be familiar with the correct procedures.

■■■■

ÂÂ

Since assets held for personal use are a matter of individual discretion, the focus is on those assets held for the production of current income or for potential appreciation.

ÂÂ

Many doctors have over time developed substantial amounts of retirement assets. In developing an investment portfolio, these assets must be an integral part of the overall design.

ÂÂ

Financial advisors should develop well-reasoned, sensible investment policies designed to achieve the client’s realistic and specified long-term investment objectives.

ÂÂ

Client should define his or her need for long-term policies to achieve long-term objectives or short-term policies to cope with short-term needs.

ÂÂ

Determine timeframe against which an investor should measure the worth of his investment policy, and what rate of return should be expected.

ÂÂ

Indian Tax payers can use CII (Cost Inflation Index) to reduce taxes. CII helps in inflating the cost of the acquired asset and thus help tax payers to show lower gains.

ÂÂ

LTCG on stocks/stock mutual funds will be tax exempted only if STT is paid. If STT is not paid, for example, if stocks are traded using off-market trades, LTCG tax is payable and not exempted.

ÂÂ

Indian tax laws do not allow the investors to use any other method than first in first out (FIFO) in demat account. So, it is tax payer’s responsibility to keep the cost basis of all the lots they bought and sold in chronological order and use it for tax computation.

ÂÂ

Both short-term and long-term losses can be carried forward and adjusted in eight years time. The Income Tax Return has a chart to enter tax losses for the preceding eight years only.

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2013

Medilaw

What are the Legal Aspects of Over-the-counter Sale of Allopathic Medicines? MC Gupta

ÂÂ

The term “over-the-counter drugs (OTC drugs)” is a loose and legally undefined term. It does not find a mention in the Drugs and Cosmetics Act, 1940, or the Drugs and Cosmetics Rules, 1945. Before discussing the legal aspects of OTC drugs, this term needs to be defined.

New products that conform to a final monograph may be marketed without further FDA review. Those that do not conform must be reviewed by the New Drug Application process. A drug company may also petition to change a final monograph to include additional ingredients or to modify labeling.”

ÂÂ

The United States Department of Food and Drug Administration (FDA) defines OTC drugs as “drugs that are safe and effective for use by the general public without seeking treatment by a health professional”. The role of FDA in regulation of OTC drugs is as follows:

http://www.fda.gov/drugs/developmentapproval process/howdrugsaredevelopedandapproved/ approvalapplications/over-the-counterdrugs/default.htm

ÂÂ

The scope/examples of OTC drugs are described by the FDA as follows:

“Over-the-counter (OTC) medicines are drugs you can buy without a prescription. Some OTC medicines relieve aches, pains and itches. Some prevent or cure diseases, like tooth decay and athlete’s foot. Others help manage recurring problems, like migraines.

In the United States, the Food and Drug Administration decides whether a medicine is safe enough to sell overthe-counter. Taking OTC medicines still has risks. Some interact with other medicines, supplements, foods or drinks. Others cause problems for people with certain medical conditions. If you’re pregnant, talk to your healthcare provider before taking any medicines.

It is important to take medicines correctly, and be careful when giving them to children. More medicine does not necessarily mean better. You should never take OTC medicines longer or in higher doses than the label recommends. If your symptoms don’t go away, it’s a clear signal that it’s time to see your healthcare provider.”

h t t p : / / w w w. n l m . n i h . g o v / m e d l i n e p l u s / overthecountermedicines.html

ÂÂ

The Wikipedia has this to say about OTC drugs:

“OTC drugs are medicines that may be sold directly to a consumer without a prescription from a healthcare professional, as compared to prescription drugs, which may be sold only to consumers possessing a valid prescription. In many countries, OTC drugs are selected by a regulatory agency to ensure that they are ingredients that are safe and effective when used without a physician’s care. OTC drugs are usually regulated

“Drug Applications for OTC Drugs

Over-the-counter (nonprescription) drug products play an increasingly vital role in America’s healthcare system. OTC drugs are defined as drugs that are safe and effective for use by the general public without seeking treatment by a health professional. FDA’s review of OTC drugs is primarily handled by CDER’s Office of Drug Evaluation IV. The Nonprescription Drug Advisory Committee meets regularly to assist the agency in evaluating issues surrounding these products. This committee has played a major role in the growth of prescription to OTC switches in recent years.

Because there are over 3,00,000 marketed OTC drug products, FDA reviews the active ingredients and the labeling of over 80 therapeutic classes of drugs, for example analgesics or antacids, instead of individual drug products. For each category, an OTC drug monograph is developed and published in the Federal Register. OTC drug monographs are a kind of ‘recipe book’ covering acceptable ingredients, doses, formulations and labeling. Many of these monographs are found in section 300 of the Code of Federal Regulations. Once a final monograph is implemented, companies can make and market an OTC product without the need for FDA pre-approval. These monographs define the safety, effectiveness and labeling of all marketing OTC active ingredients.

Advocate and Medicolegal Consultant, New Delhi

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Medilaw by active pharmaceutical ingredients (APIs), not final products. By regulating APIs instead of specific drug formulations, governments allow manufacturers freedom to formulate ingredients, or combinations of ingredients, into proprietary mixtures.

ÂÂ

The term over-the-counter may be somewhat counterintuitive, since, in many countries, these drugs are often located on the shelves of stores like any other packaged product. In contrast, prescription drugs are almost always passed over a counter from the pharmacist to the customer. Some drugs may be legally classified as over-the-counter (i.e., no prescription is required), but may only be dispensed by a pharmacist after an assessment of the patient’s needs and/or the provision of patient education. In many countries, a number of OTC drugs are available in establishments without a pharmacy, such as general stores, supermarkets, gas stations, etc. Regulations detailing the establishments where drugs may be sold, who is authorized to dispense them, and whether a prescription is required vary considerably from country to country.”

Those permitted to sell drugs under a licence can sell two types of drugs, namely, Prescription Drugs and Non Prescription Drugs. The Prescription Drugs are those drugs, which are listed in Schedule H, which is titled as Prescription Drugs. In accordance with Rule 65(9), such drugs can be sold only on the basis of a prescription issued by a Registered Medical Practitioner as defined in Rule 2(ee) of the D&C Rules, 1945. In view of the Supreme Court’s judgment in Mukhtiar Singh case, the definition of a Registered Medical Practitioner as defined in Rule 2(ee) of the D&C Rules, 1945, now means, for practical purposes, a person having a degree in modern medicine. In terms of Rule 123, drugs listed in Schedule K of the D&C Rules, 1945, do not need a licence for sale if sold by shop other than a chemist’s shop. Drugs in Schedule K include the following:

http://en.wikipedia.org/wiki/Over-the-counter_ drug

Drugs not intended for medicinal use

Quinine and other antimalarial drugs

The crucial question is - To which counter are we referring when we use the term - “over the counter”?

Magnesium sulfate

Substances intended to be used for destruction of vermin or insects, which cause disease in human beings or animals viz. Insecticides and Disinfectants.

Household remedies, namely:

Are we referring to the sales counter of a pan wallah, grocer or a general store (as is the implied meaning of this term in USA)?

Are we referring to the sales counter of a chemist/ druggist, pharmacist etc.?

It is obvious that the term OTC refers to those drugs, which can be bought across the counter at a grocery or general store etc. which can stock and sell certain drugs without obtaining any license required under the D&CA in terms of section 18(c) in chapter 4 of the D&CA, 1940, which states that - ‘no person shall sell, any drug [except under, and in accordance with the conditions of, a license issued for such purpose under this Chapter’.

Thus any drug to which chapter 4 of the D&C Act, 1940, applies cannot be sold by a grocer or general store, etc.

ÂÂ

It appears that the scheme of the Indian Drugs and Cosmetics Act/Rules is as follows:

All drugs except those listed in Schedule K of the D&C Rules, 1945, need a licence (in terms of Rule 65), permitting them to be sold.

◊

Aspirin tablets

◊

Paracetamol tablets

◊

Analgesic balms

◊

Antacid preparations

◊

Gripe water for use of infants

◊

Inhalers, containing drugs for treatment of cold and nasal congestion

◊

Syrups, lozenges, pills and tablets for cough.

◊

Liniments for external use

◊

Skin ointments and ointments for burns

◊

Absorbent cotton wool, bandages, absorbent gauze and adhesive plaster.

◊

Castor oil, liquid Paraffin and Epsom salt.

Indian Journal of Clinical Practice, Vol. 23, No. 12, May 2013

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2013

Medilaw ◊

Eucalyptus oil

◊

Tincture iodine, Tincture Benzoin Co. and Mercurochrome solution in containers not exceeding 100 ml.

◊

first aid

Tablets of Iodochlorohydroxy quinoline - 250 mg.

Contraceptives

Cosmetics

Ophthalmic ointments of the tetracycline group of drugs

Hair fixers

Radio pharmaceuticals

Tablets of chloroquine salts

Preparations applied to human body for the purpose repelling insects like mosquitoes

Medicated dressings and bandages for

Oral rehydration salts

White or yellow petroleum jelly IP (nonperfumed)

Morphine tablets

First Aid Kit supplied along with motor vehicle

the

manufacturer

its

distributor at the time of first sale of vehicle zz

Nicotine gum containing upto 2 mg of nicotine.

ÂÂ

In view of the above, it is clear that the term OTC drugs would mean, in the context of Indian laws, drugs in Schedule K. The main drugs in Schedule K have been listed above.

■■■■

Q. What is the Medicolegal Responsibility of the Hospital Management when a Medicolegal Patient from a Foreign Country Dies? What should be Done if the Relatives do not Take Away the Body? What are the Requirements for Embalming of the Body? Ans. ÂÂ

If it is a medicolegal case, it is obvious that the police would already be in the picture. If such a patient, whether an Indian or foreigner, dies, it is for the police to take further action. The role of the hospital would be to shift the body to the mortuary till the police takes action. It is not the headache of the hospital to worry about how to dispose of the body if relatives do not come forward to claim it.

ÂÂ

Hospital forensic medicine department and the hospital advocate should be kept involved. They might, in specific circumstances, advise the hospital administrator to inform the concerned government authorities (Health Directorate; Ministry). The hospital has no responsibility for embalming the body unless requested to do against payment.

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eMedinewS Inspiration

A Sweet Lesson on Patience MC Gupta

NYC Taxi driver wrote: I arrived at the address and honked the horn. After waiting a few minutes I honked again. Since this was going to be my last ride of my shift I thought about just driving away, but instead I put the car in park and walked up to the door and knocked. ‘Just a minute’, answered a frail, elderly voice. I could hear something being dragged across the floor. After a long pause, the door opened. A small woman in her 90s stood before me. She was wearing a print dress and a pillbox hat with a veil pinned on it, like somebody out of a 1940s movie. By her side was a small nylon suitcase. The apartment looked as if no one had lived in it for years. All the furniture was covered with sheets. There were no clocks on the walls, no knickknacks or utensils on the counters. In the corner was a cardboard box filled with photos and glassware. ‘Would you carry my bag out to the car?’ she said. I took the suitcase to the cab, and then returned to assist the woman.

She had me pull up in front of a furniture warehouse that had once been a ballroom where she had gone dancing as a girl. Sometimes she’d ask me to slow in front of a particular building or corner and would sit staring into the darkness, saying nothing. As the first hint of sun was creasing the horizon, she suddenly said, ‘I’m tired. Let’s go now’. We drove in silence to the address she had given me. It was a low building, like a small convalescent home, with a driveway that passed under a portico. Two orderlies came out to the cab as soon as we pulled up. They were solicitous and intent, watching her every move. They must have been expecting her. I opened the trunk and took the small suitcase to the door. The woman was already seated in a wheelchair. ‘How much do I owe you?’ She asked, reaching into her purse. ‘Nothing,’ I said

She took my arm and we walked slowly toward the curb.

‘You have to make a living,’ she answered. ‘There are other passengers,’ I responded.

She kept thanking me for my kindness. ‘It’s nothing’, I told her. ‘I just try to treat my passengers the way I would want my mother to be treated.’

Almost without thinking, I bent and gave her a hug. She held onto me tightly.

‘Oh, you’re such a good boy, she said. When we got in the cab, she gave me an address and then asked, ‘Could you drive through downtown?’ ‘It’s not the shortest way,’ I answered quickly. ‘Oh, I don’t mind,’ she said.’ I’m in no hurry. I’m on my way to a hospice. I looked in the rear-view mirror. Her eyes were glistening. ‘I don’t have any family left,’ she continued in a soft voice. ‘The doctor says I don’t have very long.’ I quietly reached over and shut off the meter. ‘What route would you like me to take?’ I asked. For the next two hours, we drove through the city. She showed me the building where she had once worked as an elevator operator. We drove through the neighborhood, where she and her husband had lived when they were newly weds.

‘You gave an old woman a little moment of joy,’ she said. ‘Thank you.’ I squeezed her hand, and then walked into the dim morning light. Behind me, a door shut. It was the sound of the closing of a life. I didn’t pick up any more passengers that shift. I drove aimlessly lost in thought. For the rest of that day, I could hardly talk. What if that woman had gotten an angry driver, or one who was impatient to end his shift? What if I had refused to take the run, or had honked once, then driven away? On a quick review, I don’t think that I have done anything more important in my life. We’re conditioned to think that our lives revolve around great moments. But great moments often catch us unaware-beautifully wrapped in what others may consider a small one.

Indian Journal of Clinical Practice, Vol. 23, No. 12, May 2013

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Confederation of Medical Associations in Asia and Oceania

Be Human Stop Child Abuse What should I do if I am sexually assaulted? ÂÂ

Find a safe place away from the person who attacked you.

ÂÂ

Call a close friend or family member. Choose someone who will give you support no matter what.

ÂÂ

Call your doctor or go to the emergency room.

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The doctor might also offer you medicines that can reduce your chances of getting pregnant (if you are a woman) or getting an infection.

ÂÂ

If you say it’s OK, the doctor can take samples of cells or fluid from your body and clothes. These samples can show who your attacker was and what he or she did.

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You do not have to let the doctor or nurse do anything you do not want.

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Do NOT try to clean up before you see a doctor or nurse. If you clean up, you might wash away proof of what happened

ÂÂ

Do not change clothes

ÂÂ

Do not take a shower or bath

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Do not brush your teeth

ÂÂ

Do not wash the inside of your vagina or rectum

ÂÂ

If you can wait, try not to go to the bathroom or to eat anything until after you have seen a doctor or nurse

ÂÂ

Find a counselor - someone you can talk to about what happened.

ÂÂ

Talk to your counselor about filing a police report.

ÂÂ

See your doctor or nurse again 1-2 weeks later. This gives them a chance to make sure everything is OK.

ÂÂ

Ask about ‘victim compensation services’.

ÂÂ

Protect others if you might have an infection. If you have sex with someone after being raped, use a condom every time you have sex for at least three months.

Shocking: 336% rise in child rape cases in India since 2001 Child rape cases in India have witnessed 336% rise since 2001. Citing National Crimes Record Bureau (NCRB) figures, the report by Asian Centre for Human

Rights (ACHR) stated that 48,338 child rape cases were recorded during 2001-11, which was an increase of 336% in such cases since 2001 when only 2,113 child rape cases were recorded. The number rose to 7,112 cases in 2011. With 9,465 cases, Madhya Pradesh was on the top of the child rape table, followed by Maharashtra (6,868) and Uttar Pradesh (5,949), while Daman and Diu (9), Dadra and Nagar Haveli (15) and Nagaland (38) reported the least number of child rape cases during 2001-11. These are only the tip of the iceberg as the large majority of child rape cases are not reported to the police while children regularly become victims of other forms of sexual assault too. The report - “India’s Hell Holes: Child Sexual Assault in Juvenile Justice Homes” stated that sexual offences against children in India had reached epidemic proportions and a large number of such crimes were being committed in 733 juvenile justice homes run and aided by government. It cited 39 such cases - 11 from government-run juvenile justice homes and 27 from privately/NGO-run ones. There were hundreds of unregistered child care homes across the country despite the requirement to register such homes within six months under Juvenile Justice (Care & Protection of Children) Act, 2006, it said, demanding registration of cases against those running unregistered juvenile justice homes. According to the report, though there were 462 District Child Welfare Committees in 23 States mandated to verify fit institutions, majority of them existed only on paper. It said lack of segregation on the basis of gender, nature of offences and age facilitated senior inmates to commit offences against minor inmates, including girls. ACHR recommended immediate establishment of Inspection Committees in all the districts and mandatory inspection of the juvenile justice homes by these committees in every three months; stopping funds to any home unless inspection reports are submitted; separate budgetary allocations for the functioning of the Inspection Committees and ban on posting of male staff in girls’ homes. Source: Hindustan Times, New Delhi, April 20, 2013

Indian Journal of Clinical Practice, Vol. 23, No. 12, May 2013

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Around the Globe

News and Views Road to HIV vaccine hits another speed bump Human immunodeficiency virus (HIV) experts reacted with dismay and resignation to the news that the National Institute of Allergy and Infectious Diseases halted its HIV Vaccine Trials Network 505 trial because it wasn’t working. (Source: Medpage Today) Pacing both ventricles best for heart block Biventricular pacing improves outcomes compared with standard right ventricular pacing for patients with atrioventricular block and depressed left ventricular ejection fraction, according to a randomized trial. (Source: Medpage Today) Incidence of cancer higher in WTC rescue workers

Older age predicts better response to Alzheimer’s drugs Cholinesterase inhibitor drugs were most effective in a real-world clinical setting the older the patients were and the higher the cognitive functioning at baseline, a Taiwanese study of patients with Alzheimer’s disease (AD) presented here shows. Chi-Ying Lin, MD, from the Dept. of Neurology at the Taipei Veterans General Hospital in Taipei, Taiwan, said his study results suggest that early diagnosis and prompt initiation of drug therapy can give better outcomes. The findings were presented here the Alzheimer’s Disease International (ADI) 28th International Conference. (Source: Medscape) Need vitamin D? Try mushrooms

In ongoing registry study, the incidence rates of all cancers combined among World Trade Center rescue workers were found to be 15% higher than expected. (Source: Medpage Today)

Eating mushrooms may be as effective at raising serum vitamin D levels as taking capsuled supplements, researchers reported at the joint American Society for Biochemistry and Molecular Biology and the Experimental Biology meeting in Boston. (Source: Medpage Today)

Candida: New rapid blood test could cut mortality

Medical interns spend very little time at patient bedsides

A new, rapid test for Candida infections of the bloodstream may reduce mortality from 40% to 11%. Researchers combined polymerase chain reaction (PCR) and nanotechnology with T2 magnetic resonance (T2MR) technology to create an assay that identifies 5 common species of Candida fungus in just three hours, which is upto 25 times faster than the current gold standard of blood culture. (Source: Medscape)

Medical interns spend only 12% of their time examining and talking with patients, and more than 40% of their time on computer tasks, according to a time-motion study published online April 18 in the Journal of General Internal Medicine. (Source: Medscape)

ECG worthwhile for pre-sports check-up Two European studies state that ECG screening of students before participation in sports to pick up potentially fatal cardiac problems is useful. (Source: Medpage Today) Living near freeway may clog arteries As per a population-based study, living near heavy traffic holds double trouble for arteries, with independent effects from road noise and air pollution on atherosclerosis. (Source: Medpage Today)

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Indian Journal of Clinical Practice, Vol. 23, No. 12, May 2013

CABG has slim edge over PCI for survival Coronary artery bypass graft (CABG) surgery was associated with a slightly lower death rate than percutaneous coronary intervention (PCI), a comparative-effectiveness study suggests. (Source: Medpage Today) Chickens pegged as source of H7N9 flu Evidence from a single patient infected with the novel avian influenza virus H7N9 points to transmission from live poultry, Chinese researchers reported. The finding suggests that live poultry could be the source of the H7N9 outbreak, which has sickened 108 people in eastern China and killed 22 according to the latest

Around the globe official update from the World Health Organization. Investigations into the source are ongoing. (Source: Medpage Today) Damaged medical bed covers pose infection risk, FDA warns Damaged or worn covers on medical bed mattresses pose a risk for contamination and infection, the US Food and Drug Administration (FDA) warned today in a safety communication. (Source: Medscape) Global alliance will target CVD prevention A global alliance for cardiovascular disease (CVD) prevention is in the works to tackle the World Health Organization’s (WHO) goal of a 25% reduction in premature, noncommunicable disease deaths by 2025, national and international society leaders announced. The proposed organization would focus on clinical practice rather than advocacy, and act somewhat like a house of representatives for the various cardiovascular professional societies, Stephan Gielen, MD, president of the European Association for Cardiovascular Prevention and Rehabilitation (EAPCR) explained. (Source: Medpage Today) Antibiotic combos don’t improve survival in P. aeruginosa bacteremia An empirical combination of antibiotics is no better than monotherapy for Pseudomonas aeruginosa bloodstream infection, Spanish researchers report. (Source: Medscape) Excess alcohol tied to diabetes precursor Prediabetes in younger patients with early-stage hypertension may be one more risk to add to the list for heavy drinking, a study showed. (Source: Medpage Today) ‘Shaking’ the heart enhances stem-cell therapy in chronic HF: CELLWAVE In a study of patients with chronic postinfarction heart failure, a procedure that involved pretreating the heart with shock waves before administering autologous bone-marrow-derived mononuclear cells (BMCs) led to modestly improved left ventricular ejection fraction (LVEF) at four months. These findings from CELLWAVE, a Phase 1/2 randomized clinical trial, are published in the April 17, 2013 issue of the Journal of the American Medical Association. (Source: Heartwire)

PIL for 50% non-doctors in medical councils To make medical councils in India ‘unbiased’ and ‘corruption-free’, NGO People for Better Treatment (PBT) will file a public interest litigation (PIL) to get non-doctors into the council. “Every medical board in the US has 50% non-doctors as members. In India, it is all a doctor’s group. We are planning to bring a PIL soon on this,” Said PBT president Dr Kunal Saha. According to the US-based doctor, corruption in the medical fraternity can be prevented if India takes up initiatives that ensure professionals other than doctors are allowed to be a part of medical groups. “The Indian government has to understand why this shielding and corruption is happening because all are from the same fraternity,” Dr Saha said. (IANS) FDA Issue Warning about ezogabine The US Food and Drug Administration (FDA) is warning that the anti-seizure medication ezogabine can cause blue skin discoloration and eye abnormalities characterized by pigment changes in the retina. (Source: Medscape) New diabetes guidelines have it both ways A new guideline from the American Association of Clinical Endocrinologists (AACE) calls for a tailored approach to treating type 2 diabetes while maintaining the use of an algorithm-based model. (Source: Medpage Today) Mediterranean diet eaten away by economic woes? A trial subanalysis has observed that the health benefits of the Mediterranean diet come at a financial cost, which may be contributing to falling adherence even in the areas where the pattern of eating is traditional. (Source: Medpage Today) Patient photo reduces errors between x-ray image sets Adding a photograph of a patient to an X-ray image increases the probability that radiologists will detect labeling errors without requiring any additional interpretation time. (Source: Medscape) Transvaginal ultrasound best to find ectopic pregnancy Transvaginal sonography may be the single best diagnostic method to evaluate suspected ectopic pregnancy in women with abdominal pain or vaginal bleeding during early pregnancy. (Source: Medpage Today)

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eMedi Quiz

Quiz Time Q1. Discharge instructions for a patient with a newlyplaced pacemaker include avoiding:

c. The client clamps the catheter drainage tubing while visiting with the family.

a. Cellular phones

d. The client loops the drainage tubing below its point of entry into the drainage bag.

b. Contact sports c. Cordless phones d. Microwave ovens Q2. An 8-month-old is admitted to the pediatric unit following a fall from his high chair. The child is awake, alert and crying. Nurse Fatima should know that a brain injury is more severe in children because of: a. Increased myelination b. Intracranial hypotension c. Cerebral hyperemia d. A slightly thicker cranium Q3. When a female client with an indwelling urinary (Foley) catheter insists on walking to the hospital lobby to visit with family members, Nurse Rose teaches how to do this without compromising the catheter. Which client action indicates an accurate understanding of this information? a. The client sets the drainage bag on the floor while sitting down. b. The client keeps the drainage bag below the bladder at all times.

Q4. A female client has just been diagnosed with Condylomata acuminata (genital warts). What information is appropriate to tell this client? a. This condition puts her at a higher risk for cervical cancer; therefore, she should have a Papanicolaou (Pap) smear annually. b. The most common treatment is metronidazole, which should eradicate the problem within 7-10 days. c. The potential for transmission to her sexual partner will be eliminated if condoms are used every time they have sexual intercourse. d. The human papillomavirus (HPV), which causes Condylomata acuminata, can’t be transmitted during oral sex. Q5. Nurse Dave is conducting an examination of a 6-month-old baby. During the examination, the nurse should be able to elicit which reflex? a. Babinski’s b. Startle c.. Moro’s d. Dance

Answers to eMedi Quiz Published in April 2013 Issue Q1. (b) Fluid overload Q2. (b) Fluid intake should be approximately equal to the urine output. Q3. (a) Kidney Q4. (d) Assessing present elimination patterns of erythropoietin. Q5. (c) Sitting in an infant seat

Send your answers to the Editor-Indian Journal of Clinical Practice. E-mail: editorial@ijcp.com The correct answers will be published in the next issue of IJCP.

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Indian Journal of Clinical Practice, Vol. 23, No. 12, May 2013

Humor

Laugh-A-While

Doctor: “Nurse, how is that little boy doing, the one who swallowed ten quarters?” Nurse: “No change yet.”

Patient: Doctor, I have yellow teeth, what do I do? Dentist: Wear a brown tie...

Share Broker Patient: Doctor, what should I do if my temperature goes up a point or more?

Patient: My hair keeps falling out.

Doctor: Sell!

What can you give me to keep it in? Doctor: A shoebox.

Indian Journal of Clinical Practice, Vol. 23, No. 11 April 2013

875

lighter reading

Lighter Side of Medicine Quote

Make Sure

During Medical Practice A patient intolerant to penicillin was denied rheumatic prophylaxis.

“We are all travelers in the wilderness of the world, and the best that we can find in our travels is an honest friend.” −Robert Louis Stevenson

Mind Trivia Oh my God! Why was he not put on a sulfa drug?

1. What number comes next?

2, 2, 4, 12, 48, ___

2. What is the next number in this series?

1, 2, 6, 42, 1806?

11111121113122223222

Make sure that patients who cannot tolerate penicillin are put on sulfadiazine or sulfisoxazole. This antibiotic class is effective for preventing Group A streptococcal (GAS) infection although it cannot be used to achieve eradication. KK Aggarwal

Dr. Good & Dr. Bad Situation: A child presented with focal convulsions

with onset of high-grade fever.

These are not simple febrile convulsions

Lesson: Simple benign febrile convulsions are always

generalized.

Dr KK Aggarwal

876

8, 5, 4, 9, 1, 7, 6, 10, 3, 2, 0

5. Which two numbers are missing and where do they go in the sequence?

8, 11, 5, 14, 1, 7, 6, 10, 13, 3, 12, 2

Ans. (1) 240. (2) To get the next number, multiply the previous number in the series by itself plus one: n * (n+1). For example, to get 6, multiply 2 * 2+1. To get 42 multiply 6 * 6+1. Thus, 1806 * 1807 = 3263442. (3) The syllables in the numbers from 1 to 20. (4) It’s the numbers 0 through 10 in alphabetical order. (5) The missing numbers are 4 and 9. The list is sorted alphabetically by the English spelling of the numbers, so four belongs after five and nine comes after fourteen.

ILLUSION

©IJCP Academy

These are simple febrile convulsions

4. What is special about the following number sequence?

Indian Journal of Clinical Practice, Vol. 23, No. 12, May 2013

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 –

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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.

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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,

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.

Indian Journal of Clinical Practice, Vol. 23, No. 12, May 2013

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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.

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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.____________

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. –

878

The legend must include enough information to permit interpretation of the figure without reference to the text.

Indian Journal of Clinical Practice, Vol. 23, No. 12, May 2013

6. Suggestions for reviewers (name and postal address)

4._ _______________

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

R.N.I. No. 50798/90 Date of Publication 13th of Same Month Date of Posting 13-14 Same Month

DL (S)-01/3200/2012-2014 Posted in N.D. PSO New Delhi