Indian journal of clinical practice october 2014 by IJCP

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ISSN 0971-0876

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Volume 25, Number 5

October 2014, Pages 401â&#x20AC;&#x201C;500

Peer Reviewed Journal

American Family Physician

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ENT

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

Volume 25, Number 5, October 2014 from the desk of THE group editor-in-chief

405 Updates in Medicine

Dr Deepak Chopra Chief Editorial Advisor Padma Shri, Dr BC Roy National & DST National Science Communication Awardee

Dr KK Aggarwal Group Editor-in-Chief

Dr Veena Aggarwal MD, Group Executive Editor

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

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

American Family Physician

407 Transient Ischemic Attack: Part I. Diagnosis and Evaluation

B. Brent Simmons, Barbara Cirignano, Annette B. Gadegbeku

412 Practice Guidelines CARDIOLOGY

414 Recent Advances in the Management of Pulmonary Hypertension

Geetha Subramaniyan, Dharmendra Jain, Balaji Lohiya, Neeraj Kumar

DERMATOLOGY

416 Cutaneous Leishmaniasis Mimicking Pyoderma Gangrenosum

Patrick Yesudian, S Murugusundram

ENDOCRINOLOGY

418 Myxedema: A Common Post Sterility Sequel in Women

Avinash Shankar, Shubham, Anuradha Shankar

424 Approach to Tall Stature

Parin N Parmar, Aarti M Makwana, Palak T Hapani, Mitul B Kalathia, SK Doshi

ENT

429 Clinical Study of Headache in Relation to Sinusitis and its Management

Anupama Kaur, Amanpreet Singh

INTERNAL MEDICINE

437 Diagnosis and Management of Chronic Cough due to Extrapulmonary Etiologies

KN Mohan Rao

444 Acute Onset Hypokalemic Quadriparesis with Dengue Fever: A Case Report

Praveen Kumar, Kalpana Chandra, Amit Varshney

OBSTETRICS AND GYNECOLOGY

449 Subclinical Hypothyroidism During Pregnancy: A Clinical Review

Rajat Mohanty, Sudipta Patnaik, Babita Ramani

455 Incidence of First Trimester Miscarriage among Women Undergoing ICSI According to Origin of Sperm for Male Factor and Non-male Factor

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

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KK Aggarwal

Alka Gahlot, ML Swarankar, Ravikant Soni

460 Predictive Value of Endometrial Thickness, Pattern

and E2 Level on Day of hCG Administration in IVF-ET Cycles Alka Gahlot, ML Swarankar, Ravikant Soni

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

466 Correlation Between D&C, USG and Hysteroscopy Findings in Diagnosing a Cause for Abnormal Uterine Bleeding

Ridhi Kathuria, Beena Bhatnagar

PEDIATRICS

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

471 Neonatal Bartter Syndrome

Meetu Rawat Gupta, Subandhu Gupta, Anand S Vasudev, RN Srivastava

474 Familial Hypercholesterolemia: Report of a Family

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Suprabha Shukla, Dillip kumar Das, Narayan Prasad Modi

Surgery

477 Surgical Treatment of Obesity and Diabetes

PG Raman

481 Unusual Presentation of Lipoma: A Case Report

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Suryapratap Singh

Around the Globe

485 News and Views EXPERT VIEW

488 How to Manage Hypertension in a Patient with Acute Heart Attack?

KK Aggarwal, RK Arora

mediLAW

490 Real Consent and not Informed Consent Applicable in India (Part II)

KK Aggarwal

INSPIRATIONAL Story

494 Blue Hummingbird lighter reading

495 Lighter Side of Medicine

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Updates in Medicine Preventing a wet cast According to an observational laboratory study comparing various methods to prevent a wet cast concluded that abstaining from contact with water is the most prudent approach; but, enclosing the cast in two plastic bags, one over the other, and sealing each bag to the skin with duct tape is an effective and inexpensive method to maintain a dry cast. This approach was substantially more effective than using a single plastic bag sealed with either a rubber band or duct tape, and equally effective as expensive commercial products.1 Anticoagulation to prevent placenta-mediated complications TIPPS (Thrombophilia in Pregnancy Prophylaxis Study), a multinational open-label randomized trial undertaken in 36 tertiary care centers in five countries concluded that antepartum prophylactic dalteparin does not reduce the occurrence of venous thromboembolism, pregnancy loss or placenta-mediated pregnancy complications in pregnant women with thrombophilia at high-risk of these complications and is associated with an increased risk of minor bleeding.2 Initial imaging in patients with suspected nephrolithiasis In patients presenting to an emergency department with suspected nephrolithiasis, initial imaging with ultrasonography was associated with lower cumulative radiation exposure than initial CT, without significant differences in high-risk diagnoses with complications, serious adverse events, pain scores, return emergency department visits or hospitalizations. The incidence of high-risk diagnoses with complications in the first 30 days was low and did not vary according to imaging method.3 Pneumococcal conjugate vaccine in adults ≥65 years of age The 23-valent pneumococcal polysaccharide vaccine (PPSV23) has been recommended for many years in the United States for all adults ≥65 years of age. In September 2014, the United States Advisory Committee on Immunization Practices (ACIP) also began recommending the pneumococcal conjugate vaccine (PCV13) for all adults ≥65 years of age.4 Pelvic examination in asymptomatic women A clinical practice guideline from the American College of Physicians (ACP) has recommended against performing screening pelvic examination in asymptomatic, nonpregnant, adult women (strong recommendation, moderate-quality evidence). The target audience for this guideline includes all clinicians, and the target patient population includes asymptomatic, nonpregnant, adult women.5 The American College of Obstetricians and Gynecologists (ACOG)

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from the desk of THE group editor-in-chief continues to recommend annual pelvic examination for asymptomatic, low-risk, nonpregnant women age 21 years and older, but suggests that the decision about whether to perform a pelvic examination be a shared decision between healthcare provider and patient, based on her own individual needs, requests and preference.6 Screening for hepatitis B virus infection The updated US Preventive Services Task Force statement on screening for hepatitis B virus (HBV) infection in nonpregnant adolescents and adults recommends that persons at high-risk for infection should be screened for HBV infection. High-risk groups include individuals born in highly endemic areas (regions with a prevalence of HBV ≥2%), HIV positive status, injection drug users, household contacts or sexual partners of persons with HBV infection, men who have sex with men and persons receiving hemodialysis or cytotoxic or immunosuppressive therapy.7 References 1. McDowell M, Nguyen S, Schlechter J. A comparison of various contemporary methods to prevent a wet cast. J Bone Joint Surg Am 2014;96(12):e99. 2. Rodger MA, Hague WM, Kingdom J, Kahn SR, Karovitch A, Sermer M, et al; for the TIPS Investigators. Antepartum dalteparin versus no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS): a multinational open-label randomised trial. Lancet 2014 Jul 24. [Epub ahead of print] 3. Smith-Bindman R, Aubin C, Bailitz J, Bengiamin RN, Camargo CA Jr, Corbo J, et al. Ultrasonography versus computed tomography for suspected nephrolithiasis. N Engl J Med 2014;371(12):1100-10. 4. Tomczyk S, Bennett NM, Stoecker C, Gierke R, Moore MR, Whitney CG, et al. Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine Among Adults Aged ≥65 Years: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2014;63(37):822-5. 5. Qaseem A, Humphrey LL, Harris R, Starkey M, Denberg TD; Clinical Guidelines Committee of the American College of Physician. Screening pelvic examination in adult women: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2014;161(1):67-72. 6. ACOG Practice Advisory on Annual Pelvic Examination Recommendations. Available at: http://www.acog.org/AboutACOG/News-Room/College-Statements-and-Advisories/2014/ACOG-Practice-Advisory-on-Annual-Pelvic-ExaminationRecommendations (Accessed on July 01, 2014)]. 7. LeFevre ML, U.S. Preventive Services Task Force. Screening for hepatitis B virus infection in nonpregnant adolescents and adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2014;161(1):58-66. ■■■■

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American Family Physician

Transient Ischemic Attack: Part I. Diagnosis and Evaluation B. BRENT SIMMONS, BARBARA CIRIGNANO, ANNETTE B. GADEGBEKU

Abstract Transient ischemic attack is defined as transient neurologic symptoms without evidence of acute infarction. It is a common and important risk factor for future stroke, but is greatly underreported. Common symptoms are sudden and transient, and include unilateral paresis, speech disturbance, and monocular blindness. Correct and early diagnosis of transient ischemic attack versus mimicking conditions is important because early interventions can significantly reduce risk of future stroke. Nonspecific symptoms and gradual onset are more likely with mimics than with true transient ischemic attacks. Transient ischemic attacks are more likely with sudden onset, focal neurologic deficit, or speech disturbance. Urgent evaluation is necessary in patients with symptoms of transient ischemic attack and includes neuroimaging, cervicocephalic vasculature imaging, cardiac evaluation, blood pressure assessment, and routine laboratory testing. The ABCD2 (age, blood pressure, clinical presentation, diabetes mellitus, duration of symptoms) score should be determined during the initial evaluation and can help assess the immediate risk of repeat ischemia and stroke. Patients with higher ABCD2 scores should be treated as inpatients, whereas those with lower scores are at lower risk of future stroke and can be treated as outpatients.

Keywords: Transient ischemic attack, early diagnosis, urgent evaluation, stroke

ver the past 10 years, transient ischemic attack (TIA) has been redefined multiple times to reflect the transient nature of not only the symptoms, but also cerebral ischemia. The classic definition for TIA of a sudden, focal neurologic deficit for less than 24 hours was established in the 1960s and was the accepted definition for 40 years.1,2 In 2002, the TIA Working Group redefined TIA as brief neurologic dysfunction with symptoms typically lasting less than one hour, without evidence of acute infarction.1 This definition was well received; however, it has been shown that no time cutoff can reliably predict if cerebral ischemia is reversible.3 This led to the 2009 revision by the American Heart Association/American Stroke Association (AHA/ASA), which now defines TIA as a transient episode of neurologic dysfunction caused by focal cerebral, spinal cord, or retinal ischemia, without acute infarction.2 A lack of evidence of infarction on magnetic resonance imaging (MRI) in patients who

B. BRENT SIMMONS, MD, FAAFP, is an assistant professor in the Department of Family, Community and Preventive Medicine at Drexel University College of Medicine in Philadelphia, Pa. BARBARA CIRIGNANO, MD, is a resident in the Department of Family, Community and Preventive Medicine at Drexel University College of Medicine. ANNETTE B. GADEGBEKU, MD, is an assistant professor in the Department of Family, Community and Preventive Medicine at Drexel University College of Medicine. Source: Adapted from Am Fam Physician. 2012;86(6):521-526.

have symptoms consistent with cerebral ischemia distinguishes TIA from minor stroke. This article, part I of a two-part series, focuses on the diagnosis of TIA. Part II discusses treatment after TIA.4 Epidemiology Using imaging results instead of a time cutoff to diagnose TIA will impact interpretation of future and past epidemiologic data on incidence and prevalence of TIA. One study evaluated MRI in patients with TIA based on the classic definition and found that 33 percent had evidence of cerebral infarction.5 Under the new definition, those with evidence of infarction should be redefined as having a stroke, leading to a lower overall incidence of TIA.5 However, TIA is likely underreported. In a telephone survey, 2.3 percent of individuals reported that they were told by their physician that they had a TIA, but an additional 3.2 percent of patients reported having symptoms consistent with TIA but never sought medical attention.6 The overall incidence of TIA is estimated to be 200,000 to 500,000 cases per year.2 TIA is a major risk factor for future ischemic stroke, with the greatest risk occurring in the period immediately after TIA.7-9 The odds ratio for ischemic stroke following TIA is 30.4 during the first 30 days, 18.9 at one to three months, 3.16 at four to six months, and 1.87 after five years.7

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American Family Physician TIA Mimics

Table 1. Clinical Symptoms of TIA Mimics

One of the greatest challenges family physicians face when evaluating possible TIA is distinguishing true TIA and ischemic events from TIA mimics. Physician accuracy in determining this distinction in the outpatient primary care setting historically has been poor, and a study showed that even stroke-trained neurologists have a fair amount of disagreement when diagnosing TIA.10,11

Clinical symptom

Correct and early diagnosis of TIA versus mimics is critical because early interventions (e.g., antiplatelet agents, statin therapy, blood pressureâ&#x20AC;&#x201C;lowering therapy, anticoagulation when appropriate) can lead to an 80 percent reduction in risk of recurrent ischemic events.12 The most common TIA mimics are seizures, migraines, metabolic disturbances, and syncope.10,13,14 Mimics are more likely with gradual onset of symptoms and with nonspecific symptoms (Table 113), such as memory loss or headache.13-15 TIA is more likely with sudden onset, unilateral paresis, speech disturbance, or transient monocular blindness.13,14,16 Table 2 shows which symptoms are more likely with mimics versus true TIA.13,14 A complete history and physical examination are necessary to correctly diagnose TIA in the outpatient setting. Presentation

History At initial presentation, a comprehensive history should include identification of symptoms consistent with a focal neurologic deficit, and the timing of symptom onset and resolution. This is crucial because symptoms often resolve by the time of presentation. Attention should also be given to the presence or absence of nonspecific symptoms common in TIA mimics. Witnesses of the event can also be helpful in describing symptoms not perceived by the patient. The history should elicit risk factors associated with ischemic disease, such as cigarette smoking, obesity, diabetes mellitus, dyslipidemia, and hypertension, as well as personal or family history of hypercoagulability disorders, stroke, or TIA. Symptoms of TIA occur suddenly and include a neurologic deficit or loss of function.17 It is imperative to ask about recurrent symptoms of TIA because recent, recurrent TIA (crescendo TIA) requires urgent evaluation. Mimics are more common in patients with a history of cognitive disorders, seizures, postural hypotension, and vertigo.10,14 Symptoms that generally are not suggestive of TIA include generalized weakness, dizziness, confusion, loss of consciousness, tinnitus, dysphagia, scotoma, headache, eye pain, and chest

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Odds ratio of a TIA mimic

Memory loss

9.17

Headache

3.71

Blurred vision

2.48

Unilateral paresis

0.35

Transient monocular blindness

0.15

Diplopia

0.14

Note: The higher the odds ratio is above 1.0, the more likely the symptom is due to a TIA mimic; the lower the odds ratio is below 1.0, the more likely the symptom is due to a TIA or stroke. TIA = Transient ischemic attack. Information from reference 13.

Table 2. Clinical Symptoms of TIA vs. TIA Mimics Clinical symptom

Percentage of TIA mimics*

Unilateral paresis Memory loss/ cognitive impairment Headache

Percentage of TIAs*

29.1

18 to 26

2 to 12

14.6 to 23

2 to 36

Blurred vision

21.8

5.2

Dysarthria

12.7

20.6

Hemianopia

3.6

Transient monocular blindness

Diplopia

4.8

TIA = Transient ischemic attack. *When clinical symptoms are present at presentation. Information from references 13 and 14.

pain.17,18 It is important to note that the presence of common mimic symptoms does not exclude TIA from the diagnosis; however, mimics should be considered in the absence of concurrent focal deficits. Table 3 presents the differential diagnosis of TIA.

Physical Examination A clinical presentation that demonstrates motor weakness and speech deficits is highly suggestive of TIA, and also may be associated with a higher risk of having an early stroke after TIA.19 The physical examination should include measurement of vital signs, a cardiovascular examination, and a comprehensive neurologic examination. Blood pressure is commonly elevated with cerebral ischemia and should be assessed, along with an evaluation for carotid bruits or cardiac arrhythmias. Careful attention should be given to focal neurologic deficits and their represented neurovascular

American Family Physician Table 3. Differential Diagnosis of Transient Ischemic Attack Diagnosis

Key findings

Brain tumor

Severe unilateral headache with nausea and vomiting

Central nervous system infection (e.g., meningitis, encephalitis)

Fever, headache, confusion, neck stiffness, nausea, vomiting, photophobia, change in mental status

Falls/trauma

Headache, confusion, bruising

Hypoglycemia

Confusion, weakness, diaphoresis

Migraines

Severe headaches with or without photophobia, younger age

Multiple sclerosis

Diplopia, limb weakness, paresthesia, urinary retention, optic neuritis

Seizure disorder

Confusion with or without loss of consciousness, urinary incontinence, tongue biting, tonicclonic movements

Subarachnoid hemorrhage

Severe headache with sudden onset and photophobia

Vertigo (central or peripheral)

Generalized dizziness and diaphoresis with or without hearing loss

distribution. Cranial nerve, somatic motor strength, somatic sensory, speech and language, and cerebellar system testing should be performed. The most common findings for TIA in the cranial nerve examination are diplopia, hemianopia, monocular blindness, disconjugate gaze, facial drooping, lateral tongue movement, dysphagia, and vestibular dysfunction.17,18 Cerebellar system testing includes ocular movement and finger-to-nose and heel-to-shin movement, which may reveal nystagmus, pastpointing, dystaxia, or ataxia. Motor testing suggestive of TIA may reveal spasticity, clonus, rigidity, or unilateral weakness in the upper or lower extremities, face, and tongue. Unilateral weakness and speech disturbance are the most common presenting symptoms in patients with TIA, and these symptoms are more likely to be associated with acute cerebral infarction on MRI.20,21 In an analysis of persons with TIA, 31 to 54 percent presented with focal weakness, 25 to 42 percent presented with speech changes, 16 to 32 percent had symptoms lasting one hour or less, and 37 to 72 percent had symptoms lasting more than one hour.3 Evaluation The diagnostic evaluation of suspected TIA should be initiated as soon as possible to stratify risk of recurrent events. According to AHA/ASA guidelines, the goals of the diagnostic evaluation are to evaluate the vasculature for the mechanism and origin of the patientâ&#x20AC;&#x2122;s symptoms and to exclude nonischemic etiologies.2 Symptomatic patients should be considered as having an active stroke and evaluated urgently in an emergency department.

Imaging The AHA/ASA recommends neuroimaging within 24 hours of symptom onset. Diffusion-weighted MRI is

the preferred modality because it is more sensitive than computed tomography (CT).2 However, CT is more commonly used than MRI because of its availability and ability to quickly identify intracerebral hemorrhage.22 If a patient receives an emergent CT, a follow-up MRI should be performed when available because of its superiority in identifying cerebral infarction.2 The presence of infarction on MRI can have important prognostic implications. A study of classically defined TIA showed that patients with infarction on MRI had an in-hospital stroke rate of 19.4 percent, compared with 1.3 percent in those without evidence of infarction.23 Using the new definition, many patients with classically defined TIA would be redefined as having a minor stroke if there is evidence of acute infarction on MRI. A recent study used the new definition of TIA to evaluate patients whose symptoms resolved within 24 hours. For those with evidence of infarction on MRI (now defined as minor stroke), 7.1 percent had a stroke within the next seven days, compared with just 0.4 percent of patients without evidence of infarction.24 In patients with TIA, the cervicocephalic vasculature should be assessed for treatable atherosclerotic lesions using carotid ultrasonography/transcranial Doppler ultrasonography, magnetic resonance angiography, or CT angiography.2 A reasonable approach is to perform carotid imaging within one week of symptom onset in patients who are candidates for carotid endarterectomy.25 A metaanalysis showed that magnetic resonance angiography had 92.2 percent sensitivity and 75.7 percent specificity for the diagnosis of carotid stenosis, compared with 87.5 percent sensitivity and 75.7 percent specificity with carotid ultrasonography.26 Another study demonstrated 81 percent sensitivity and 96 percent specificity with CT angiography, compared with 92 percent sensitivity and 98 percent specificity with magnetic resonance angiography.27

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American Family Physician Cardiac Assessment Electrocardiography should be performed during the initial evaluation. Transthoracic or transesophageal echocardiography can be used to look for a cardioembolic source and to determine the presence of patent foramen ovale, valvular disease, cardiac thrombus, and atherosclerosis.2 Prolonged cardiac monitoring with telemetry in the inpatient setting or Holter monitor in the outpatient setting is reasonable, primarily to evaluate for paroxysmal atrial fibrillation.

Laboratory Testing In the initial evaluation of TIA symptoms, blood glucose and serum electrolyte levels should be measured to help rule out hypoglycemia or an electrolyte imbalance as the cause of change in mental status. Complete blood count and coagulation studies can help determine the likelihood of hemorrhage and thrombotic disorders.2,28 For younger patients and when there is clinical suspicion of central nervous system infection, drug intoxication, or clotting disorders, additional workup to assess the potential contribution of these disorders should include rapid plasma reagin testing, cerebrospinal fluid examination, urine drug screening, and full hypercoagulability workup.2,28 A fasting lipid panel should be performed to determine cardiovascular risk and for baseline cholesterol levels, to determine the appropriate starting dose of statin therapy needed to achieve target low-density lipoprotein levels.2 Risk Stratification and Hospitalization Criteria The ABCD2 (age, blood pressure, clinical presentation, diabetes mellitus, duration of symptoms) score (Table 419) is a modified version of the original ABCD score, which was developed to determine stroke risk following TIA.19,29 The ABCD2 score has been shown to be highly predictive of the severity of stroke; higher scores correlate with higher disability and length of hospitalization.30 Additionally, a population-based study of TIA demonstrated that the ABCD2 score is highly predictive of a stroke occurring within 24 hours.29 In this study, 76 percent of patients with a recurrence had an ABCD2 score of 5 or greater.31 In a recent study, an emergency department used the ABCD2 score in a novel triage protocol. Patients with an ABCD2 score of 0 to 3 were discharged from the emergency department with an appointment for outpatient MRI and magnetic resonance angiography and an appointment with an outpatient neurologybased TIA clinic within two business days. Those with a score of 4 or 5 received cervical and intracranial vessel

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Table 4. ABCD2 Scoring System for Evaluating Stroke Risk After TIA Clinical characteristics

Points

Age ≥ 60 years

Blood pressure: systolic ≥ 140 mm Hg or diastolic ≥ 90 mm Hg

Clinical presentation Unilateral weakness

Speech impairment without weakness

Diabetes mellitus

Duration of TIA ≥ 60 minutes

10 to 59 minutes

Note: Risk of stroke at two days: 1 to 3 points = low risk (1 percent); 4 or 5 points = moderate risk (4.1 percent); 6 or 7 points = high risk (8.1 percent). TIA = Transient ischemic attack. Information from reference 19.

imaging in the emergency department. If a symptomatic lesion was identified, they were admitted. If no lesion was identified, they were discharged with the followup appointments. All patients with an ABCD2 score greater than 5 were admitted. This approach led to lower rates of admission and lower-than expected rates of recurrent stroke, which are consistent with expedited specialized outpatient management.32 This is a practical approach that can be instituted at most facilities. However, if urgent imaging is not available through the emergency department or if urgent outpatient neurology follow-up is not available, it is reasonable to admit for observation any patient with an ABCD2 score of 3 or greater who presents within 72 hours of symptom resolution, who has evidence of focal ischemia, or who cannot complete outpatient workup within 48 hours.2,29-31 Anyone with active signs or symptoms or any intracranial lesion on imaging should be considered as having a stroke and managed accordingly. REFERENCES 1. Albers GW, Caplan LR, Easton JD, et al.; TIA Working Group. Transient ischemic attack—proposal for a new definition. N Engl J Med. 2002;347(21):1713-1716. 2. Easton JD, Saver JL, Albers GW, et al. Definition and evaluation of transient ischemic attack. Stroke. 2009;40(6):2276-2293. 3. Shah SH, Saver JL, Kidwell CS, et al. A multicenter pooled, patient level data analysis of diffusion-weighted MRI in TIA patients [abstract]. Stroke. 2007;38(2):463.

American Family Physician 4. Simmons BB, Cirignano B, Gadegbeku AB. Transient ischemic attack: part II. Risk factor modification and treatment. Am Fam Physician. 2012;86(6):527-532.

20. Cucchiara BL, Messe SR, Taylor RA, et al. Is the ABCD score useful for risk stratification of patients with acute transient ischemic attack? Stroke. 2006;37(7):1710-1714.

5. Ovbiagele B, Kidwell CS, Saver JL. Epidemiological impact in the United States of a tissue-based definition of transient ischemic attack. Stroke. 2003;34(4):919-924.

21. Crisostomo RA, Garcia MM, Tong DC. Detection of diffusion-weighted MRI abnormalities in patients with transient ischemic attack: correlation with clinical characteristics. Stroke. 2003;34(4):932-937.

6. Johnston SC, Fayad PB, Gorelick PB, et al. Prevalence and knowledge of transient ischemic attack among US adults. Neurology. 2003;60(9):1429-1434. 7. Thacker EL, Wiggins KL, Rice KM, et al. Short-term and long-term risk of incident ischemic stroke after transient ischemic attack. Stroke. 2010;41(2):239-243. 8. Hill MD, Yiannakoulias N, Jeerakathil T, Tu JV, Svenson LW, Schopflocher DP. The high risk of stroke immediately after transient ischemic attack: a population-based study. Neurology. 2004;62(11):2015-2020. 9. Kleindorfer D, Panagos P, Pancioli A, et al. Incidence and short-term prognosis of transient ischemic attack in a population-based study. Stroke. 2005;36(4):720-723.

22. Edlow JA, Kim S, Pelletier AJ, Camargo CA Jr. National study on emergency department visits for transient ischemic attack, 1992-2001. Acad Emerg Med. 2006;13(6):666-672. 23. Ay H, Koroshetz WJ, Benner T, et al. Transient ischemic attack with infarction: a unique syndrome? Ann Neurol. 2005;57(5):679-686. 24. Giles MF, Albers GW, Amarenco P, et al. Early stroke risk and ABCD2 score performance in tissue- vs timedefined TIA: a multicenter study. Neurology. 2011;77(13): 1222-1228.

10. Ferro JM, Falc찾o I, Rodrigues G, et al. Diagnosis of transient ischemic attack by the nonneurologist. A validation study. Stroke. 1996;27(12):2225-2229.

25. Swain S, Turner C, Tyrrell P, Rudd A; Guideline Development Group. Diagnosis and initial management of acute stroke and transient ischaemic attack: summary of NICE guidance. BMJ. 2008;337:a786.

11. Castle J, Mlynash M, Lee K, et al. Agreement regarding diagnosis of transient ischemic attack fairly low among stroke-trained neurologists. Stroke. 2010;41(7):1367-1370.

26. Nederkoorn PJ, Mali WP, Eikelboom BC, et al. Preoperative diagnosis of carotid artery stenosis: accuracy of noninvasive testing. Stroke. 2002;33(8):2003-2008.

12. Rothwell PM, Giles MF, Chandratheva A, et al. Effect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke (EXPRESS study): a prospective population-based sequential comparison [published correction appears in Lancet. 2008;371(9610):386]. Lancet. 2007;370(9596):1432-1442.

27. Magarelli N, Scarabino T, Simeone AL, et al. Carotid stenosis: a comparison between MR and spiral CT angiography. Neuroradiology. 1998;40(6):367-373.

13. Amort M, Fluri F, Sch채fer J, et al. Transient ischemic attack versus transient ischemic attack mimics: frequency, clinical characteristics and outcome. Cerebrovasc Dis. 2011;32(1):57-64. 14. Hand PJ, Kwan J, Lindley RI, Dennis MS, Wardlaw JM. Distinguishing between stroke and mimic at the bedside: the brain attack study. Stroke. 2006;37(3):769-775. 15. Prabhakaran S, Silver AJ, Warrior L, McClenathan B, Lee VH. Misdiagnosis of transient ischemic attacks in the emergency room. Cerebrovasc Dis. 2008;26(6):630-635. 16. Sheehan OC, Merwick A, Kelly LA, et al. Diagnostic usefulness of the ABCD2 score to distinguish transient ischemic attack and minor ischemic stroke from noncerebrovascular events: the North Dublin TIA Study. Stroke. 2009;40(11):3449-3454. 17. Shah KH, Edlow JA. Transient ischemic attack: review for the emergency physician. Ann Emerg Med. 2004;43(5): 592-604.

28. Adams HP Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists [published corrections appear in Stroke. 2007;38(9):e96, and Stroke. 2007;38(6):e38]. Stroke. 2007;38(5):1655-1711. 29. Rothwell PM, Giles MF, Flossmann E, et al. A simple score (ABCD) to identify individuals at high early risk of stroke after transient ischaemic attack. Lancet. 2005;366(9479): 29-36. 30. Chandratheva A, Geraghty OC, Luengo-Fernandez R, Rothwell PM; Oxford Vascular Study. ABCD2 score predicts severity rather than risk of early recurrent events after transient ischemic attack. Stroke. 2010;41(5): 851-856.

18. Albucher JF, Martel P, Mas JL. Clinical practice guidelines: diagnosis and immediate management of transient ischemic attacks in adults. Cerebrovasc Dis. 2005;20(4):220-225.

31. Chandratheva A, Mehta Z, Geraghty OC, Marquardt L, Rothwell PM; Oxford Vascular Study. Population-based study of risk and predictors of stroke in the first few hours after a TIA. Neurology. 2009;72(22):1941-1947.

19. Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack. Lancet. 2007;369(9558):283-292.

32. Olivot JM, Wolford C, Castle J, et al. Two aces: transient ischemic attack work-up as outpatient assessment of clinical evaluation and safety. Stroke. 2011;42(7): 1839-1843.

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American Family Physician

Practice Guidelines Updated Guidelines from AASM for the Treatment of Central Sleep Apnea Syndromes Central sleep apnea syndromes are characterized by sleep-disordered breathing associated with absent or diminished respiratory effort. Symptoms include excessive daytime sleepiness, frequent waking during the night, or both. This practice parameter reviews available data on the treatment of central sleep apnea syndromes in adults. The American Academy of Sleep Medicine (AASM) includes levels of recommendations (standard or option) based on the overall quality of evidence (high, moderate, low, or very low).

Treatment of Primary Central Sleep Apnea Syndromes Positive airway pressure therapy may be considered for the treatment of primary central sleep apnea syndromes. (Option.) Positive airway pressure therapy includes continuous positive airway pressure (CPAP), bi-level positive airway pressure in a spontaneous timed mode, and adaptive servo-ventilation. Adaptive servo-ventilation is a type of closed-loop mechanical ventilation that provides a breath-by-breath adjustment of inspiratory pressure support to regulate breathing patterns relative to a preset target. Although the literature is limited, positive airway pressure therapy can improve central respiratory events without significant risks, and is readily available. The quality of evidence for this recommendation is very low. Acetazolamide has limited supporting evidence, but may be considered for the treatment of primary central sleep apnea syndromes. (Option.) The overall quality of evidence for this recommendation is low. Use of acetazolamide has the potential to produce adverse effects, such as paresthesias, tinnitus, gastrointestinal symptoms, metabolic acidosis, electrolyte imbalance, and drowsiness. The use of zolpidem and triazolam may be considered for the treatment of primary central sleep apnea syndromes only if the patient does not have underlying risk factors for respiratory depression. (Option.) There is limited

Source: Adapted from Am Fam Physician. 2012;86(10):968-971.

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available evidence for this recommendation. Use of these medications may produce adverse effects, such as respiratory depression, and should be considered only as a last therapeutic option if other options are unsuccessful. Close clinical follow-up is required for patients using these hypnotic agents.

Syndromes due to CHF, Including Cheyne Stokes Breathing Pattern and not Cheyne Stokes Breathing CPAP therapy targeted to normalize the apnea-hypopnea index is indicated for the initial treatment of central sleep apnea syndromes related to congestive heart failure (CHF). (Standard.) The overall quality of evidence for this recommendation is moderate, but with a large effect size and consistent findings reducing the apnea-hypopnea index and improving left ventricular ejection fraction. Data show that CPAP treatment targeted to an apneahypopnea index less than 15 has a positive effect on transplant-free survival in patients with central sleep apnea syndromes and CHF. This treatment is readily available, and health care professionals are familiar with its use; therefore, it warrants a standard level of recommendation. If central sleep apnea syndromes caused by CHF are not controlled, other treatment options should be considered. Bi-level positive airway pressure therapy in a spontaneous timed mode targeted to normalize the apnea-hypopnea index may be considered for the treatment of central sleep apnea related to CHF only if there is no response to adequate trials of CPAP, adaptive servo ventilation, and oxygen therapies. (Option.) In the limited number of available studies, spontaneous timed mode was used more often than spontaneous mode. Bi-level positive airway pressure therapy in a spontaneous timed mode has similar advantages to CPAP (e.g., low risk, readily available). However, because of the shortage of evidence, it should be considered only in patients who do not respond to CPAP, adaptive servo-ventilation and oxygen therapy. It also is considerably more expensive than CPAP, and it requires specialized expertise. Adaptive servo-ventilation targeted to normalize the apneahypopnea index is indicated for the treatment of central sleep apnea syndromes related to CHF. (Standard.) The evidence for this recommendation is of moderate quality. Data

American Family Physician show that adaptive servo-ventilation improves the apnea-hypopnea index and the left ventricular ejection fraction; however, there are no long-term or survival data available. It is difficult to generalize findings because many studies are industry sponsored, and manufacturers use different algorithms to detect respiratory events and evaluate pressure delivery. Also, there is uncertainty about the optimum settings of the devices. Although more expensive than CPAP, adaptive servo-ventilation has produced consistent data that are comparable or better than the data for CPAP.

of standard medical therapy, if positive airway pressure is not tolerated and if accompanied by close clinical follow-up. (Option.)

Nocturnal oxygen therapy is indicated for the treatment of central sleep apnea syndromes related to CHF. (Standard.) Data show that nocturnal oxygen therapy reduces the apnea-hypopnea index and improves the left ventricular ejection fraction, although studies varied in the duration of treatment. Oxygen therapy is not superior to CPAP, but it is easily administered and may be used in persons with central sleep apnea syndromes related to CHF who cannot comply with CPAP therapy.

Syndromes due to Other Medical Conditions: EndStage Renal Disease

Acetazolamide and theophylline have limited supporting evidence, but may be considered for the treatment of central sleep apnea syndromes related to CHF after optimization

Data supporting these agents are limited, and the balance of benefits and harms are unclear. Potential adverse effects from theophylline include cardiac arrhythmias, central nervous system excitability, and gastrointestinal symptoms. Theophylline has a narrow therapeutic index and requires close monitoring of levels.

The following possible treatment options for central sleep apnea syndromes related to end stage renal disease may be considered: CPAP, supplemental oxygen, bicarbonate buffer use during dialysis, and nocturnal dialysis. (Option.) The level of evidence for this recommendation is very low, and the balance of benefits and harms is unclear for any specific therapy in this population. Bicarbonate buffer is preferable during hemodialysis in these patients, although more research is needed to determine the effectiveness of the other therapies.

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413

CARDIOLOGY

Recent Advances in the Management of Pulmonary Hypertension GEETHA SUBRAMANIYAN*, DHARMENDRA JAIN†, BALAJI LOHIYA‡, NEERAJ KUMAR‡

Abstract Pulmonary arterial hypertension (PAH) is a life-threatening and progressive disease characterized by pulmonary vascular remodeling that leads to increased pulmonary vascular resistance and pulmonary arterial pressure, most often resulting in right-sided heart failure. Originally considered to be a disorder of vasoconstriction and vasodilatation, it has become clear that the predominant characteristic of PAH is abnormal cellular proliferation leading to progressive obliteration of the pulmonary vasculature. Current PAH-specific therapies target one of three major pathways involved in development and progression of PAH: 1) The endothelin pathway targeted by the endothelin receptor antagonists (ERAs); 2) the prostacyclin pathway, targeted by prostacyclin analogs and 3) the nitric oxide (NO) pathway, targeted by the phosphodiesterase type 5 (PDE-5) inhibitors.

Keywords: Pulmonary arterial hypertension, endothelin receptor antagonist, prostacyclin analogs, phosphodiesterase type 5 inhibitors

ulmonary arterial hypertension (PAH) is a lifethreatening and progressive disease of various origins characterized by pulmonary vascular remodeling that leads to increased pulmonary vascular resistance and pulmonary arterial pressure, most often resulting in right-sided heart failure. The most common symptom at presentation is breathlessness, with impaired exercise capacity as a hallmark of the disease. Advances in understanding the pathobiology over the last two decades have led to therapies (endothelin receptor antagonists, phosphodiesterase type 5 (PDE-5) inhibitors and prostacyclins or analogs) initially directed at reversing the pulmonary vasoconstriction and more recently directed toward reversing endothelial cell dysfunction and smooth muscle cell proliferation. The dual endothelin receptor antagonist (ERA), bosentan, is an orally active therapy, which is effective in the treatment of PAH.

*Emeritus Professor Dr MGR Medical University, Chennai, Tamil Nadu †Assistant Professor Dept. of Cardiology ‡DM Fellow Institute of Medical Sciences, Banaras Hindu University Varanasi, Uttar Pradesh Address for correspondence Dr Dharmendra Jain C-2, New Medical Enclave, Near Naria Gate Institute of Medical Sciences, Banaras Hindu University Varanasi, Uttar Pradesh - 221 005 E-mail: djaincard@gmail.com

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Although associated with a range of underlying etiologies, all forms of PAH share a common pulmonary arteriopathy characterized by vasoconstriction, remodeling of the pulmonary vessel wall and thrombosis in situ. Originally considered to be a disorder of vasoconstriction and vasodilatation, it has become clear that the predominant characteristic of PAH is abnormal cellular proliferation leading to progressive obliteration of the pulmonary vasculature. There has, therefore, been an increasing interest over the past decade not only in agents, which act as effective vasodilators; but also in those; which have antiproliferative and antiremodeling effects. Current PAHspecific therapies target one of three major pathways involved in development and progression of PAH: 1) The endothelin pathway targeted by the ERAs; 2) the prostacyclin pathway, targeted by prostacyclin analogs and 3) the nitric oxide (NO) pathway, targeted by the PDE-5 inhibitors. While it is probable that further advances can be made using existing therapies (e.g., as part of combination regimens or in specific patient populations), there is also the need for the development of new treatment options, with improved efficacy, safety, tolerability and/ or convenience profiles. There are two approaches that can be taken to develop new agents for continued improvements in the treatment of PAH: 1) New, more efficacious or more convenient drugs that act on established pathways already targeted by existing PAH-specific therapies

CARDIOLOGY and 2) agents targeting novel pathogenic pathways that are emerging as a result of continued basic scientific research in the field. NEW AGENTS TARGETING ESTABLISHED PATHWAYS IN PAH

Endothelin Pathway Macitentan Macitentan is an oral dual (endothelin [ETA] and ETB) ERA designed to have improved tissue penetration due to an increased proportion of the nonionized form of the molecule, which is able to cross lipophilic cell membranes.

Nilotinib Nilotinib is a second-generation oral tyrosine kinase inhibitor that was specifically designed to overcome the problems of resistance to imatinib, which can develop during therapy for CML. In this setting, nilotinib has a more favorable safety profile than imatinib, although it is associated with a risk of cardiac complications, including QT prolongation and sudden cardiac death.

Serotonin Receptor Antagonists Terguride

Prostacyclin Pathway

Terguride modulates a range of neurotransmitter receptors including dopamine, α2-adrenergic receptors and serotonin. It is a strong anti-serotoninergic drug, acting as an antagonist of the 5-HT2 receptors, which have been implicated in pathogenesis of PAH.

Selexipag

CONCLUSION

Selexipag is an orally available prostacyclin IP receptor agonist which, as a diphenylpyrazine derivative, is chemically distinct from prostacyclin and prostacyclin analogs. Oral treprostinil Oral treprostinil is a novel salt form of treprostinil (treprostinil diethanolamine), delivered via sustained release tablet to support twice-daily dosing.

No Pathway Riociguat Soluble guanylate cyclase (sGC) is a key signaltransduction enzyme activated by endothelial cellderived NO. sGC converts guanosine 5-triphosphate to cyclic guanosine monophosphate (cGMP), leading to vasodilation and inhibition of platelet aggregation and vascular smooth cell proliferation. AGENTS TARGETING NEW PATHWAYS IN PAH

Tyrosine Kinase Inhibitors Imatinib Platelet-derived growth factor (PDGF) has been implicated in the abnormal proliferation and migration of pulmonary vascular smooth muscle cells in PAH, and lung tissue from patients with PAH has been shown to have increased expression of PDGF receptors. Imatinib is an orally administered PDGF inhibitor currently licensed for the treatment of chronic myelogenous leukemia (CML) and certain gastrointestinal tumors.

Significant advances continue to be made in PAH. New therapies are awaiting approval which offer more ways of fighting the disease. Intense research is ongoing and aimed at exploring novel pathways in treating the disease. SUGGESTED Reading 1. Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2009;34(6):1219-63. 2. McLaughlin VV. Looking to the future: a new decade of pulmonary arterial hypertension therapy. Eur Respir Rev 2011;20(122):262-9. 3. Iglarz M, Binkert C, Morrison K, et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther 2008;327(3):736-45. 4. Ghofrani HA, Voswinckel R, Gall H, et al. Riociguat for pulmonary hypertension. Future Cardiol 2010;6(2):155-66. 5. Barst RJ. PDGF signaling in pulmonary arterial hypertension. J Clin Invest 2005;115(10):2691-4. 6. Kantarjian H, Giles F, Wunderle L, Bhalla K, O’Brien S, Wassmann B, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006;354(24):2542-51. 7. Keegan A, Morecroft I, Smillie D, Hicks MN, MacLean MR. Contribution of the 5-HT(1B) receptor to hypoxia-induced pulmonary hypertension: converging evidence using 5-HT(1B)-receptor knockout mice and the 5-HT(1B/1D)receptor antagonist GR127935. Circ Res 2001;89(12):1231-9. 8. Launay JM, Hervé P, Peoc’h K, et al. Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension. Nat Med 2002;8(10):1129-35.

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DERMATOLOGY

Cutaneous Leishmaniasis Mimicking Pyoderma Gangrenosum Patrick Yesudian, S Murugusundram*

Abstract Cutaneous leishmaniasis (CL) is caused by leishmania, a single-called parasite and is transmitted the bite of sand fly. It characterized by ulcers, which are usually without pain or pruritus. Both old world and new world species cause localized CL. Old world disease begins as a small erythematous papule at the site of the bite of the sand fly and over several weeks it enlarges up to 3 cm eventually becoming eroded and crusted. After lasting for several months the ulcer heals with a slightly depressed scar. We report the case of a 27-year-old man native of South India, carpenter by occupation, working in Saudi Arabia for >5 years who presented with a painful ulcer of 10 cm in diameter over his right shoulder with purulent discharge. He was diagnosed to have CL and was treated with intramuscular injection of sodium stibogluconate 20 mg/kg/day for 30 days. The resultant cribriform scar resembled that of pyoderma gangrenosum.

Keywords: Cutaneous leishmaniasis, pyoderma gangrenosum, cribriform scar

Case Report A 27-year-old man native of South India, carpenter by occupation, working in Saudi Arabia for >5 years presented with a painful ulcer of 10 cm in diameter over his right shoulder with purulent discharge. He was treated by the native physician in his village in the form of herbal pastes, which aggravated the ulceration.

On Examination A huge round ulcer of 10 cm in diameter was seen over the posterior aspect of the right shoulder and upper one-third of the right arm. Herbal paste was covering the surface. The ulcer had an indurated base, exquisitely tender border and pus oozing out through sieve-like openings on gentle pressure (Fig. 1). Based on the morphology, the differential diagnosis considered were: ÂÂ

Superficial pyoderma

ÂÂ

Pyoderma gangrenosum

ÂÂ

Granulomatous ulcers leishmaniasis, etc.

tuberculosis,

*Founder and Medical Director Chennai Skin Foundation and Yesudian Research Institute Chennai, Tamil Nadu E-mail: smurugu@hotmail.com

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Figure 1. Pus oozing out from the ulcer.

Indian Journal of Clinical Practice, Vol. 25, No. 5, October 2014

Figure 2. Skin biopsy of the ulcer margin showing macrophagic granuloma with inclusion bodies.

DERMATOLOGY must have acquired the infection while working in the middle-east, where the disease is endemic. Old world CL begins as a small erythematous papule at the site of the bite of the sand fly. Over several weeks it enlarges up to 3 cm eventually becoming eroded and crusted. After lasting for several months the ulcer heals with a slightly depressed scar.1 Nonindigenous patients can have severe lesions due to lack of specific immunity.2

Figure 3. Resultant cribriform scar resembling pyoderma gangrenosum.

Investigation Skin biopsy from the border of the ulcer showed a macrophagic granuloma with inclusion bodies (Fig. 2). Scrapings from the edge of the ulcer revealed typical intracytoplasmic Leishmania tropica bodies on Giemsa stain. A diagnosis of cutaneous leishmaniasis was made.

Treatment and Follow-up The ulcer healed completely with intramuscular injection of sodium stibogluconate 20 mg/kg/day for 30 days. The resultant cribriform scar (Fig. 3) also resembled that of pyoderma gangrenosum. Observations In the past decade or two, with numerous South Indians (Kerala and Tamil Nadu) going to middle-east countries for jobs, it is not unusual for dermatologists practicing in South India to encounter cutaneous leishmaniasis (CL) caused by L. tropica. Our patient

Many atypical variants of CL have been described such as paronychial, chancriform, annular, palmoplantar, zosteriform, verrucous, erysipeloid and sporotrichoid.3 A similar atypical variant of CL mimicking pyoderma gangrenosum has been reported in Portuguese by Talhari et al.4 The unusual morphology and the tenderness could be due to an altered host response or involvement of an atypical strain of the parasite.3 Pyoderma gangrenosum, an inflammatory disorder of unknown etiology is mainly a clinical diagnosis, which can simulate many infections, connective tissue diseases and lymphomas. It responds to systemic steroids but not to antibiotics.5 References 1. Hepburn NC. Cutaneous leishmaniasis: an overview. J Postgrad Med 2003;49(1):50-4. 2. Momeni AZ, Aminjavaheri M. Clinical picture of cutaneous leishmaniasis in Isfahan, Iran. Int J Dermatol 1994;33(4):260-5. 3. Iftikhar N, Bari I, Ejaz A. Rare variants of cutaneous leishmaniasis: whitlow, paronychia, and sporotrichoid. Int J Dermatol 2003;42(10):807-9. 4. Talhari S, Neves RG. Leishmaniasis mimicking pyoderma gangrenosum. In: Dermatologia Tropical. de Janeiro R (Ed.), MEDSI 1995:p.44. 5. Mark Jackson J, Callen JP. Pyoderma gangrenosum: an expert commentary. Expert Rev Dermatol 2006;1(3): 391-400.

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Dermal Filler Injections may Lead to Vision Loss Some patients who get facial injections in order to look good may end up seeing very poorly as a result of retrograde occlusion of ocular arteries, warned researchers at the 14th EURETINA Congress. Researchers described six patients who received dermal filler injections in their faces and developed retrograde arterial occlusions, causing either temporary or permanent vision loss in one eye.

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417

ENDOCRINOLOGY

Myxedema: A Common Post Sterility Sequel in Women Avinash Shankar*, Shubham†, Anuradha Shankar‡

Abstract Weight gain in association with presenting symptoms like exertional dyspnea, hot flushes, leg cramps, irregular menses and exhaustion in women abstaining from pregnancy is increasing progressively and investigations affirms it as a manifestation of hypothyroidism secondary to disuse atrophy of ovary associated with altered adrenal function presenting as hyperglycemia.

Keywords: Hypothyroidism, disease atrophy of ovary, hyperglycemia

onsidering the increasing population growth and financial constraint due to rising cost of livelihood, for limitation of child birth the commonest practiced method is surgical sterilization i.e., tube ligation in female, as male usually abstain from sterilization due to prevailing concept of post vasectomy sexual debility or inability. But increasing incidence of weight gain, exertional dyspnea, hot flushes, feeling of excessive cold or hot, etc. in nonconceiving women either due to surgical sterilization of female or male, use of contraceptives inspired us to assess the pathophysiology of these presentations. Hence, a clinical study was done at RA Hospital and Research Centre, Warisaliganj (Nawada), Bihar, India to ascertain the biokinetics of these presentations.

MATERIAL and METHODS This study was conducted in 1879 women, who had undergone tube ligation presenting with complaints of: Heaviness in the body, exertional dyspnea, feeling of excessive hot and cold, hot flushes, swelling of the

*Chairman National Institute of Health and Research, Warisaliganj, Nawada, Bihar †Director Centre for Research in Children’s Disease (Presently Working at Dept. of Pediatrics) RML, PGI, New Delhi ‡Project Officer Myxedema Study Centre for Research in Endocrinology and Metabolism Address for correspondence Dr Avinash Shankar Chairman National Institute of Health and Research, Warisaliganj, Nawada, Bihar E-mail: dravinashshankar@gmail.com

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body, constipation, leg cramps, irregular menses and exhaustion. Attending medical OPD of RA Hospital and Research Centre during the period January 2000 to December 2008. Based on the complaints, patients were interrogated for obstetrical history, menstrual status, mode of sterilization and clinically the patients were thoroughly examined for body weight, blood pressure, myxedema and systemic evaluation for cardiac function. In addition patients were investigated for: ÂÂ

Urine for albumin; blood for hemoglobin, sugar, serum cholesterol and blood urea; serum level for tri-iodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH) and electrocardiography (ECG).

OBSERVATION Among the selected cases 16.39% were of age group 25-30 years, while 5.16% were of age >50 years though majority (49.4%) were of age group 30-40 years (Table 1). Common presentation among most of the patients was heaviness in the body, weight gain, exertional dyspnea, while 79.33% presented with Table 1. Age-wise Distribution of Patients Age group (years)

Number of patients

25-30

308

(16.39%)

30-35

412

35-40

517

40-45

217

(27.51%)

45-50

128

(06.81%)

>50

(05.16%)

ENDOCRINOLOGY burning sensation in extremities, hot flushes in 67.86% while sleep disturbances in 84.62% (Table 2). Five hundred seven patients had myxedema presentation within 5 years of tubal ligation, while 480 had after 10-15 years (Table 3). Majority (572) patients had tubal

ligation at the age of 25-30 years, while 522 had tubal ligation <25 years of age and 375 patients at >35 years of age (Table 4). About 26.72% cases had weight gain 1 Table 6. Shows Distribution of Patients as per Blood Pressure Status

Table 2. Shows Distribution of Patients as per their Clinical Presentation

Blood pressure

Presenting features

Number of patients

90-100

140

Heaviness in the body

1,879

101-110

878

Lethargy, weakness or tiredness

1,879

111-120

621

Ringing in the ear

1,750

121-130

240

Perspiration

1,879

Menstrual irregularities

1,800

Muscular twitching

1,680

Burning sensation in the extremity

1,500

Exertional dyspnea

1,879

Hot flushes

1,260

Sleep disturbance

1,590

Weight gain

1,879

Number of patients

Systolic pressure (mm Hg)

Diastolic pressure (mm Hg) 60-66

160

67-72

712

73-78

789

78-84

218

Table 7. Shows Distribution of Patients as per Hormonal Level Hormone index

Number of patients

T3 in

Table 3. Shows Distribution of Patients as per Time Lapse between Ligation and Clinical Presentation

<10

112

10-20

432

Time gap (in years)

Number of patients

20-30

561

01-05

507

30-40

512

05-10

892

40-50

202

10-15

480

T4 in <0.5

105

0.5-1.0

138

1.0-1.5

321

Number of patients

1.5-2.0

367

20-25

522

2.0-2.5

420

25-30

572

2.5-3.0

328

30-35

410

3.0-3.5

200

35-40

375

TSH in

Table 4. Shows Distribution of Patients as per Age at Ligation Age group (years)

6-8

208

8-10

198

10-12

122

Number of patients

12-14

206

IBW + 1 SD

502

14-16

304

IBW + 2 SD

454

16-18

402

IBW + 3 SD

788

18-20

329

IBW + 4 SD

135

>20

110

Table 5. Shows Distribution of Patients as Per Body Weight Body weight

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ENDOCRINOLOGY SD (10 kg) > ideal body weight (IBW), while 7.18% had weight gain 4 SD > IBW (Table 5). Among the selected patients 76.21% (1,432) cases had tubal ligation, while 11.39% (214) were opting for oral contraceptives, 7.24% (136) were using intrauterine device (IUD), though 4.84% (76) were with premenopausal amenorrhea and 1.12% were with postmenopausal amenorrhea. Clinical examination revealed hypotension (systolic in 7.45% and diastolic in 8.52%) though majority revealed normotensive state (Table 6). ECG tracing showed low voltage in 66.74% cases. Biochemical estimation revealed fasting hyperglycemia (blood sugar >110 mg/dL) in 23.2% (436), all showed T3 <50, though 5.96% showed T3 <10, while 5.55% showed T4 <0.5 and 5.85% showed TSH >20 (Table 7). DISCUSSION Women abstaining pregnancy either by surgical tubal ligation, using contraceptives, oral or IUD or practicing safe sex with condom or vasectomy in male counterpart and having complaints like progressive weight gain,

heaviness in the body, exertional dyspnea, exhaustion, cold intolerance, constipation suspected as cases of myxedema and were confirmed by TSH, T3 and T4 estimation. In addition, few women revealed hyperglycemia. All these evident changes can be attributed to hormonal changes secondary to disuse atrophy of ovary leading to imbalance of estrogen and progesterone resulting in thyroid hypofunction i.e., thyroid suppression while adrenal fatigue and insulin resistance also leads to thyroid hypoactivity in few cases resulting in myxedema and hyperglycemic syndrome, while hypoactivity of parathyroid causes serum calcium alteration as all the manifestations duly responded to thyroxine and calcium administration. Estrogen diminution also inhibited thyroid activity. Reference 1. Lee JR. Estrogen deficiency and contraceptive pills consumption directly affect thyroid activity.

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Corneal Microscopy Detects Diabetic Autonomic Neuropathy Corneal confocal microscopy can detect subclinical and overt diabetic autonomic neuropathy, a new study suggests. Results from a 52-subject trial were presented September 14 at Neurodiab, the annual meeting of the Diabetic Neuropathy Study Group of the European Association for the Study of Diabetes, by optometrist Mitra Tavakoli, PhD, a research fellow at the Centre for Endocrinology & Diabetes, Institute of Human Development, University of Manchester, United Kingdom.

Long Hours in Low-Status Jobs Raises Type 2 Diabetes Risk Working long hours - at least 55 hours per week - in a job with low socioeconomic status increases the risk for type 2 diabetes by nearly 30%, a new study shows. But no effect on diabetes risk was seen in those employed in high-socioeconomic-status positions, regardless of the hours put in. The meta-analysis is published online September 25 in Lancet Diabetes & Endocrinology. Lead author Mika Kivimäki, PhD, professor of epidemiology, University College London, United Kingdom, said a remarkably clear pattern between socioeconomic status and diabetes had emerged.

Women using IVF ‘half as likely to conceive if vitamin D deficient’ A new study published in the Journal of Clinical Endocrinology & Metabolism (JCEM) finds that women who are deficient in vitamin D are half as likely to conceive using in vitro fertilization compared with women without vitamin D deficiency. Vitamin D is a steroid hormone that is produced in the skin as a consequence of exposure to the sun, and it can also be absorbed by eating certain foods. Vitamin D is essential for good bone health, but scientists are now becoming interested in the effect vitamin D may have on fertility.

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Endocrinology

Approach to Tall Stature Parin N Parmar*, Aarti M Makwana*, Palak T Hapani*, Mitul B Kalathia*, SK Doshi†

Abstract As a presenting chief complaint, tall stature represents only ‘tip of iceberg’ of all the tall children. For a pediatrician, it is very important to distinguish familial or constitutional tall stature from other pathological forms of tall stature. For practicing pediatricians, availability of literature discussing clinical approach to a child presenting with tall stature is limited. This article presents clinically simple and rational approach to tall stature.

Keywords: Tall stature, growth charts

all stature is defined as height beyond 97th percentile (i.e., over two standard deviations) of mean for age and sex. Excessive growth is defined as an abnormally rapid growth velocity, which could manifest as height acceleration across two major percentile lines on the growth chart. Although 2.5% of the population will meet the definition, due to social acceptability or even desirability of tallness (‘heightism’), tall stature is not a common complaint. As tall stature may be the initial manifestation of a serious underlying disease, it is important to distinguish tall patients who are otherwise healthy from those who have underlying pathology. Growth charts Growth charts are available for monitoring height and weight. Height charts are useful as a primary screening tool when evaluating a child with tall stature. Growth charts for body mass index (BMI), height velocity charts and proportion charts may be essential, while evaluating a child with tall stature. Velocity charts are also used to follow a child’s progress over a period of time and monitoring of treatment. Proportion charts contain sitting height and subischial leg length (SIL). These are expressed as standard deviation scores and not as percentiles. When the

*Assistant Professor †Professor and Head Dept. of Pediatrics PDU Medical College, Rajkot, Gujarat Address for correspondence Dr Parin N Parmar Niraj, 1/4, Jyotinagar, Kalawad Road, Rajkot, Gujarat - 360 005 E-mail: parinmnparmar@gmail.com

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disproportion between SIL and sitting height is more than two standard deviations, the child is considered to be disproportionate. Prediction of height Genetics, nutrition, hormones (growth hormone, thyroid hormone, estrogen and testosterone) and overall health affect human height. The growth spurt around puberty occurs around 2 years earlier in girls when compared to boys, but the boys tend to be taller when it begins. Most of the average height difference between adult men and women relates to the greater growth of boys during the adolescent growth spurt and the greater height achieved prior to the growth spurt. One simple way to predict adult height of a child is doubling the height achieved by the second birthday. Another way is to calculate mid-parental height (MPH) as follows: ÂÂ

Target height for boy = ([Father’s height + 13] + Mother’s height)/2 cm.

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Target height for girl = (Father’s height + [Mother’s height – 13])/2 cm.

MPH is an indicator of child’s genetic potential for growth. The value is plotted as adult height at 18 years and the spread for target range is 6 cm on either side of the target height (TH). This becomes the target range and if the child’s height is within these percentiles, it is considered as normal. Etiology ÂÂ

Familial (constitutional) tall stature the most common cause of tall stature in childhood.

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Nutritional: Exogenous obesity.

Endocrinology ÂÂ

Endocrine: Precocious puberty (early stage), pituitary gigantism and other causes of growth hormone excess including McCune-Albright syndrome, thyrotoxicosis, androgen/estrogen deficiency, estrogen resistance (in males), testicular feminization, adrenocorticotropic hormone (ACTH)/cortisol deficiency, ACTH/cortisol resistance and aromatase deficiency.

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Chromosomal: Klinefelter syndrome (XXY), fragile X syndrome, XYY syndrome.

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Collagen vascular: Marfan syndrome.

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Metabolic: Homocystinuria.

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Fetal overgrowth syndromes: Maternal diabetes mellitus, cerebral gigantism (Sotos syndrome), Beckwith-Wiedemann syndrome, Weaver syndrome, Simpson-Golabi-Behmel overgrowth syndrome, other insulin-like growth factor (IGF)-2 excess syndrome.

Evaluation of a child with tall stature

History As familial tall stature is the most common cause seen in childhood, information about abnormally tall parents, grandparents, uncles and cousins is essential. Apart from routine history, symptoms suggesting precocious puberty or delayed puberty should be specifically asked depending upon age of the child. Intellectual development of the child should be recorded carefully.

Physical Examination Meticulous measurement parameters of auxology including height, weight, BMI, upper segment/lower segment ratio, arm span and height/arm span ratio is essential. It will also give a clue to the etiology of tall stature. Accurate plotting of anthropometric parameters on growth chart is also necessary. It will

Suspected tall stature? Height/length >97 percentile for age and sex? Yes

Reassurance

History and physical examination Stigmata*? Present

Absent

Proportionate tall stature?

Parental height Tall

Normal

Bone age

Yes BWS weaver

Accelerated

Normal Familial/constitutional tall stature

BMI Obese

BMI = Body mass index

Yes Nonobese

Pubertal development

Exogenous obesity

Advanced

IGF-1 = Insulin-like growth factor-1

Learning/behavior problem? No

Homocystinuria Klinefelter’s XYY Sotos syndrome

Marfan eunuchoid

Normal

GH = Growth hormone TSH = Thyroid stimulating hormone

Precocious puberty

IGF-1 and GH

TSH,T3,T4

Pituitary gigantism

Hyperthyroidism

T3 = Tri-iodothyronine T4 = Thyroxine. * See table 1.

Figure 1. Evaluation of a child with tall stature.

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Endocrinology Table 1. Stigmata to Look for in Physical Examination of a Child with Tall Stature Homocystinuria

Klinefelter syndrome Marfan syndrome

Sotos syndrome1 Beckwith-Wiedemann syndrome Weaver syndrome3 Simpson-Golabi-Behmel syndrome4

Ectopia lentis, cataracts, arachnodactyly, pectus excavatum or carinatum, genu valgum, pes cavus, high arched palate, scoliosis, crowding of teeth Gynecomastia, small testes, sparse facial hair, micropenis, delayed pubertal development, cryptorchidism, hypospadias Hypotonia, joint laxity (thumb sign and wrist sign), lax skin, ectopia lentis, abnormally flat cornea, blue sclera, iridodonesis, arachnodactyly, dolichocephaly, malar hypoplasia, retrognathia, downslanting palpebral fissures, high arched palate, crowding of teeth, pectus excavatum or carinatum, scoliosis, aortic aneurysm, aortic regurgitation, mitral valve prolapsed Macrocrania, large hands and feet, thickened subcutaneous tissue, dolichocephaly, prominent jaw, hypertelorism, antimongoloid slant, clumsiness, awkward gait Hepatosplenomegaly, nephromegaly, macroglossia, omphalocele, renal malformations, ear creases/pits, facial nevus flammeus2 Broad forehead and face, ocular hypertelorism, prominent wide philtrum, micrognathia, deep horizontal chin groove, deep-set nails Large protruding jaw, widened nasal bridge, macroglossia, upturned nasal tip, coarse face, ‘bulldog-like’ appearance, supernumerary nipples, generalized muscular hypotonia, congenital heart defect

Table 2. Investigation Undertaken Depending upon the Suspected Causes Suspected cause Beckwith-Wiedemann Maternal diabetes mellitus GH excess Hyperthyroidism Homocystinuria Kleinfelter syndrome XYY syndrome Marfan syndrome Precocious puberty Central

Peripheral

Investigations Glucose, insulin, renal ultrasonography Glucose, insulin GH, IGF-1 and IGFBP-3 levels; pituitary MRI T3, T4 and TSH levels Homocysteine, methionine LH, FSH and testosterone levels; karyotyping Karyotyping Clinical diagnosis; fibrillin-1 gene mutation Bone age; LH, FSH, estradiol and testosterone levels; GnRH analog stimulation test Bone age; 17 α-hydroxyprogesterone, hCG, DHEAS, estradiol and testosterone levels; cosyntropin stimulation test

GH = Growth hormone; IGF-1 = Insulin-like growth factor-1; IGFBP-3 = Insulin-like growth factor binding protein-3; MRI = Magnetic resonance imaging; T3 = Tri-iodothyronine; T4 = Thyroxine; TSH = Thyroid stimulating hormone; LH: Luteinizing hormone; FSH = Follicle stimulating hormone; GnRh = Gonadotropin releasing hormone; hCG = Human chorionic gonadotropin; DHEAS = Dihydroepiandrostenedione.

also help calculating height velocity on follow-up. Crossing height percentiles between infancy and onset of puberty always warrants further evaluation. One should specifically look for signs of obesity, signs of

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precocious or delayed puberty, dysmorphism, stigmata of specific disorders known to be associated with tall stature. Tanner sexual maturity rating (SMR) should be done in all children presenting with tall stature as a routing practice. Stigmata to look for in physical examination of a child with tall stature summarized in Table 1.

investigations If history is suggestive of familial tall stature and the physical examination is entirely normal, no laboratory tests may be indicated. Otherwise investigation are undertaken depending on the suspected causes (Table 2) .

Bone Age Calculation of bone age is done by Tanner-Whitehouse and Grulich-Pyle methods. The former is preferred5 as it can assess the bone age to an accuracy of 0.1 year. Accelerated bone age is seen in precocious puberty, Sotos syndrome, Marshall-Smith syndrome, BeckwithWiedemann syndrome, etc. it also helps to predict adult height, which may help for management decisions. Additional laboratory tests should be ordered according to clues to etiology and suspected cause in a particular patient.

Familial Tall Stature It is the most common cause of tall stature seen in childhood and adolescence. The length of the child may be above average at birth. History of a very tall parent or a close relative is usually present.

Endocrinology Marfan’s Syndrome

Exogenous Obesity

This autosomal dominant condition is characterized by a low upper segment/lower segment ratio and arm span greater than height. Other features are as mentioned above. Revised Ghent nosology6 is used for diagnosis in children.

Exogenous obesity is becoming a commoner cause of tall stature in childhood due to increasing incidence of obesity in higher socioeconomical classes. High leptin levels have been found as one of the possible factors for accelerated skeletal growth.8 It is characterized by rapid linear growth and early maturation, bone age is usually modestly accelerated. As puberty and epiphyseal fusion occur early, adult height is usually normal.

Homocystinuria It is an autosomal recessive condition with many clinical features similar to those in Marfan syndrome. However, it is associated with mental retardation. Urinary amino acid analysis should be performed for diagnosis.7

Klinefelter’s Syndrome Klinefelter’s syndrome (47:XXY) is characterized by long legs and decreased upper segment/lower segment ratio. The condition causes infertility due to defective spermatogenesis and Sertoli cell function. Psychological features may range from sheer psychosocial or school adjustment difficulties to frank mental retardation. The diagnosis is possible by karyotyping. All tall boys with mental subnormality or decreased upper segment/ lower segment ratio should undergo karyotyping to exclude this syndrome.

XYY Syndrome It is less commonly seen than Klinefelter syndrome. It is also associated with behavioral and mental problems.

Precocious Puberty This is a common cause of increased height velocity presenting as tall stature in childhood and adolescence. However, accelerated linear growth is also accompanied by acceleration of skeletal maturation resulting in eventual compromised adult height.

Delayed Puberty Delayed onset of puberty is not a common cause of tall stature in children as onset of accelerated linear growth is late. However, sustained growth and delayed closure of epiphyses eventually lead to tall stature in later life.

Hyperthyroidism Hyperthyroidism is commonly seen in adolescent females and the cause is almost always Grave’s disease. It is characterized by rapid growth velocity though the adult height may be normal.

Cerebral Gigantism (Sotos Syndrome) This, mostly sporadic, condition occurs due to nonprogressive hypothalamic lesion. At birth, the patient is typically above 90th percentile for both length and weight, which is followed by rapid growth. Affected infants are over 97th percentile in height by 1 year of age. The accelerated growth continues for first 4-5 years and then returns to a normal rate. Puberty usually occurs at normal time, sometimes may occur slightly early. Adult height is usually in upper normal range. There are no distinctive laboratory or radiological markers for diagnosis of the condition. Abnormal EEGs and dilated ventricular system in neuroimaging may be seen.

Infant of Diabetic Mother Maternal diabetes is the most common cause of overgrowth in infants. They are large-for-gestational age at birth. The overgrowth is most commonly due to hyperinsulinemia.

Beckwith-Wiedemann Syndrome In addition to clinical features mentioned above, hypoglycemia secondary to pancreatic b-cell hyperplasia is common in, usually large-for-gestational age, infant. The condition predisposes the patient to Wilm’s tumor and adrenocortical carcinoma.

Growth Hormone Excess and Pituitary Gigantism Although rare in childhood, most commonly it is due to pituitary adenoma. The length of the child is usually normal at birth. Sometimes rapid growth of head may precede linear growth in young children. Although fatigue and lassitude are early symptoms, typically pituitary gigantism is characterized by coarse facial features, broad nose, enlarged tongue, excess growth of mandible, separated teeth and enlarging hands and feet. Behavioral problems, visual field

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Endocrinology defects and neurological abnormalities are also seen in some children. Serum growth hormone level is usually elevated. However, as growth hormone is secreted in a pulsatile manner, a single measurement of serum growth hormone level is inadequate to diagnose or to rule out growth hormone excess. Failure to suppress serum growth hormone level to <5 ng/dL after a 1.75 g/kg oral glucose challenge is considered gold standard for diagnosis of pituitary gigantism. Laboratory evidence of growth hormone excess mandates magnetic resonance imaging (MRI) evaluation of pituitary. IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3) levels are consistently elevated in pituitary gigantism. They are very useful as screening test.

McCune-Albright Syndrome Triad of precocious puberty, café-au-lait spots and fibrous dysplasia, is a rare condition associated with pituitary gigantism and tall stature.9 Management Reassurance to the index case and the family is the key in normal variant tall stature. Treatment with sex steroids should be considered even in familial/constitutional tall stature for following indications:10 1) Predictable adult height over three standard deviations above the mean (198 cm in males and 180 cm in females) and 2) evidence of significant psychosocial impairment. Principles of management with sex steroids: ÂÂ

Sex steroids should be started prepubertally

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In girls, oral ethinyl estradiol 0.15-0.5 mg/day is given until cessation of growth; progestational agent may be added after 1 year of unopposed estrogen administration

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Although estrogen action affects both growth hormone and IGF production, its main clinical benefit occurs due to its action on epiphysis

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As estrogen is obviously not desirable in males, androgens are used in male patients

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Androgens accelerate skeletal maturation presumably through aromatization to estrogen

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Therefore in boys, testosterone enanthate 500 mg intramuscular is given every 2 weeks for the duration of 6 months.

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Sex steroids successfully reduce the predicted adult height by 5-10 cm.

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ÂÂ

One should be cautious when using sex steroid due to its side effects, which are nausea, hypertension, acne fulminans, lipid abnormalities, menstrual irregularities, cholelithiasis, thromboembolism, etc.

Therapeutic options for management of growth hormone oversecretion are surgical (commonly transsphenoidal) removal, radiation therapy, somatostatin analogs (octreotide and lanreotide), dopamine (D2) agonist (bromocriptine) and growth hormone receptor antagonist (pegvisomant). Summary Familial tall stature is the most common cause of tall stature in children. A simplified clinical approach with optimum use of laboratory investigations to a patient with tall stature can differentiate those with familial tall stature from those with underlying disorders. Apart from treating the etiology, sex steroids are used for treatment. References 1. Cole TR, Hughes HE. Sotos syndrome. J Med Genet 1990;27(9):571-6. 2. Elliott M, Bayly R, Cole T, Temple IK, Maher ER. Clinical features and natural history of Beckwith-Wiedemann syndrome: presentation of 74 new cases. Clin Genet 1994;46(2):168-74. 3. Cole TR, Dennis NR, Huges HP. Weaver syndrome. J Med Genet 1992;29(5):332-7. 4. Neri G, Gurrieri F, Zanni G, Lin A. Clinical and molecular aspects of the Simpson-Golabi-Behmel syndrome. Am J Med Genet 1998;79(4):279-83. 5. Bull RK, Edwards PD, Kemp PM, Fry S, Hughes IA. Bone age assessment: a large scale comparison of the Greulich and Pyle, and Tanner and Whitehouse (TW2) methods. Arch Dis Child 1999;81(2):172-3. 6. Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010;47(7):476-85. 7. Carson NA, Cusworth DC, Dent CE, Field CM, Neill DW, Westall RG. Homocystinuria: a new inborn error of metabolism associated with mental deficiency. Arch Dis Child 1963;38:425-36. 8. Shalitin S, Phillip M. Role of obesity and leptin in the pubertal process and pubertal growth - a review. Int J Obes Relat Metab Disord 2003;27(8):869-74. 9. Dumitrescu CE, Collins MT. McCune-Albright syndrome. Orphanet J Rare Dis 2008;3:12. 10. Rosenfeld RG, Cohen P. Disorders of growth hormone/ insulin-like growth factor secretion and action. In: Pediatric endocrinology. 3rd edition, Sperling MA (Ed.), Elsevier: Saunders 2008:p.319.

ENT

Clinical Study of Headache in Relation to Sinusitis and its Management ANUPAMA KAUR*, AMANPREET SINGH†

Abstract Aim: To study relation of headache with sinusitis and its management. Material and methods: Patients clinically presenting with headache were selected. Only patients with headache due to rhinogenic causes were subjected to X-ray paranasal sinuses (PNS) and diagnostic nasal endoscopy (DNE) and were followed up to evaluate management. Results: Majority of the patients were of age group 21-30 years and it is more predominant in males. Majority of the patients with headache had deviated nasal septum (DNS) (28.9%), acute sinusitis (28.9%), osteomeatal complex disease (24.63%); few patients had nasal polyp (8.69%), allergic rhinitis (5.79%) and rarely patients had atrophic rhinitis (2.89%). Headache was localized in forehead (43.4%), more than one site (34.7%) in majority of cases and few number of patients had headache at glabella (13.04%) and top of head (8.69%). Majority of the patients who underwent antral washout were not relieved, so they underwent functional endoscopic sinus surgery (FESS), which gave dramatic results in improving symptoms including headache. Conclusions: Headache is nearly a universal human experience. The lifetime incidence of headache is estimated to be at least 90%. To know whether the headache is sinogenic or not, the patient is first assessed clinically and then radiological investigations (X-ray PNS) are done. Role of FESS is huge and ultimately it is FESS that is the cure for headache due to rhinogenic causes.

Keywords: Headache, sinusitis, FESS

eadache is nearly a universal human experience. The lifetime incidence of headache is estimated to be at least 90%. Moskowitz has described headache as the symptom produced by the nervous system when it perceives threat and as such is considered part of the protective physiology of the nervous system. When the cause of headache is a definable underlying pathologic process, the headache is diagnosed as a secondary headache. Causes include metabolic, infectious, inflammatory, traumatic, neoplastic, immunologic, endocrinologic and vascular entities. When no clear pathologic condition can be identified, headache is considered to be a manifestation of a primary headache syndrome. The common primary

*Assistant Professor Dept. of Physiology †Assistant Professor Dept. of ENT MM Institute of Medical Sciences and Research Mullana, Ambala, Haryana Address for correspondence Dr Amanpreet Singh Assistant Professor Dept. of ENT MM Institute of Medical Sciences and Research Mullana, Ambala, Haryana E-mail: dr.apsarora@gmail.com

headache disorders as defined by the International Headache Society are migraine, probable migraine, tension type and cluster headache.1 The term ‘sinusitis’ refers to a group of disorders characterized by inflammation of the mucosa of the paranasal sinuses (PNS). Because the inflammation nearly always also involves the nose, it is now generally accepted that ‘rhinosinusitis’ is the preferred term to describe the inflammation of the nose and PNS.2 Patients with chronic headache pain often present to a variety of specialists, including their primary care physician, neurologist, dentist, otolaryngologist and even a psychiatrist. They may present to otolaryngologist because they or their physician believe the headache to be related to underlying sinus pathology. The primary focus of the otolaryngologist is to exclude this possibility. The diagnosis of headache secondary to acute sinusitis can be relatively straightforward. Diagnosing headache related to chronic sinus disease can be much more difficult depending on patient’s presentation.3 Endoscopic techniques are now well-established. In combination with modern imaging techniques particularly computed tomography (CT), these techniques provide diagnostic possibilities unimagined a few decades ago.4

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ENT AIM To study the relation of headache in sinusitis and its management.

If the headache was suspected to be of rhinogenic or sinogenic origin, the patients then underwent detailed otorhinolaryngological examination. ÂÂ

Routine blood investigations like hemoglobin (Hb), total leukocyte count (TLC), differential leukocyte count (DLC), erythrocyte sedimentation rate (ESR), bleeding time (BT), clotting time (CT), urine for albumin, sugar and microscopy.

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Radiological investigations i.e., X-ray PNS (Water’s view) was advised in all patients of headache of rhinogenic or sinogenic etiology.

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Diagnostic nasal endoscopy (DNE) was advised to the same group of patients.

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Acute infections were first treated with medicines.

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Patients who were found to have haziness of maxillary sinuses on PNS X-ray were advised antral wash.

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Patients who had haziness of frontal sinuses and the patients who were not relieved of headache after antral washout were advised functional endoscopic sinus surgery (FESS).

MATERIAL AND METHODS The present study was conducted in the Dept. of Otorhinolaryngology in MM Medical College and Hospital, Mullana, Ambala, Haryana from October 2009 to July 2011.

Source of Data Patients for the study were collected from the Dept. of Otorhinolaryngology, MM Medical College and Hospital, Mullana, Ambala, Haryana.

Sample Size The study included 100 patients and the cases were diagnosed based upon clinical examination and investigation.

Inclusion Criteria

Exclusion Criteria All patients presenting with clinical features other than sinusitis.

Study Procedures ÂÂ

Selected patients were subjected to a complete examination according to a defined proforma.

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Detailed history with thorough clinical examination was done.

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Patients were asked about history of headache

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Mode of onset

Duration of complaint

Continuous or intermittent

Progressive or not

Site of pain and radiation

Type of pain

Associated symptoms

Aggravating and relieving factors

Duration of each attack

Frequency of attack

Time of onset of attack

Treatment taken for the same.

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RESULTS A total of 100 patients with headache were studied for a period of about 2 years i.e., from October 2009 to July 2011, of which only 69 patients had headache due to rhinogenic causes. The highest incidence was in the age group of 21-30 years (59.42%), followed by 11-20 years (36.23%) (Fig. 1, Table 1). Patients of age group 21-30 years were more prone (51.61%), to headache due to other causes (Fig. 2, Table 2). About 53.62% of patients of headache due to rhinogenic causes were males and 46.37% were females (Fig. 3, Table 3). In headache due to other causes about 16 14 No. of cases

Patients of all age groups and sexes presenting with clinical features of sinusitis.

12 10 8 6 4 2 0

5-10

11-20 21-30 31-40 Age group (years)

41-50

51-60

DNS

Acute sinusitis

Osteomeatal complex disease

Polyp

Allergic rhinitis

Atrophic rhinitis

Figure 1. Age distribution (rhinogenic causes).

ENT Table 1. Age Distribution (Rhinogenic Causes) (n = 69) Age group (years) 11-20 21-30 6 14

Male

41-50 -

51-60 -

10 8 6 4 2 0

DNS

Acute Osteomeatal sinusitis complex disease

Atrophic rhinitis

Rhinogenic causes

Figure 3. Sex distribution (rhinogenic causes).

7 No of cases

Polyp Allergic rhinitis

Table 3. Sex Distribution (Rhinogenic Causes) (n = 69)

8 6 5 4 3 2 1 0

Female

31-40 -

No. of cases

DNS Acute sinusitis Osteomeatal complex disease Polyp Allergic rhinitis Atrophic rhinitis

5-10 -

5-10

11-20

21-30

31-40

41-50

51-60

Age group (years) Trigeminal neuralgia Tension headache

Migraine

Temporomandibular joint arthritis

Male

Female

DNS

Acute sinusitis

Osteomeatal complex disease

Polyp

Allergic rhinitis

Atrophic rhinitis

Figure 2. Age distribution (others).

Male

Female

Table 2. Age Distribution (Others) (n = 31) Age group (years) 5-10

11-20

21-30

31-40

41-50

51-60

Migraine

Trigeminal neuralgia

Temporomandibular joint arthritis

Tension headache

No. of cases

8 7 6 5 4 3 2 1 0

93.54% of the patients in headache due to other causes were females and 6.45% were males (Fig. 4, Table 4). About 28.9% of patients of headache had deviated nasal septum (DNS) and 28.9% of the patients had acute sinusitis, 24.63% of the patients had osteomeatal complex disease and 8.69% of patients had polyp, 5.79% of patients had allergic rhinitis and 2.89% of patients had

Migraine

Trigeminal neuralgia

Temporomandibular joint arthritis Other causes

Tension headache

Figure 4. Sex distribution (other causes).

Table 4. Sex Distribution (Other Causes) (n = 31) Male

Female

Migraine

Trigeminal neuralgia

Temporomandibular joint arthritis

Tension headache

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ENT 20

Atrophic rhinitis (2.90%) Allergic rhinitis (5.80%) Polyp (8.70%)

18 16

DNS (28.99%)

Acute sinusitis (28.99%)

Figure 5. Etiology of headache with respect to clinical findings.

No. of cases

Osteomeatal complex disease (24.64%)

14 12 10 8 6 4 2 0

Table 5. Etiology of Headache with Respect to Clinical Findings

DNS

Acute sinusitis (under antibiotic cover) Antral washout No. of patients Relieved

OMD

Not relieved

No. of cases

Rhinogenic causes (%)

DNS

28.90

Acute sinusitis

28.90

Osteomeatal complex disease

24.63

Polyp

8.69

DNS

Allergic rhinitis

5.79

Atrophic rhinitis

2.89

Acute sinusitis (under antibiotic cover) Osteomeatal complex disease

Glabella (13.04%)

Forehead (43.48%)

Top of head (8.70%)

Figure 7. Patients who underwent antral washout.

Table 7. Patients Who Underwent Antral Washout No. of patients

Relieved (n = 20)

Not relieved (n = 37)

Completely free of pain (30%)

No benefit from surgery (33%)

More than one site (34.78%)

Figure 6. Localization of headache.

Significant symptom improvement (37%)

Table 6. Localization of Headache Localization

No. of cases

Rhinogenic causes (%)

Forehead

43.4

More than one site

34.7

Glabella

13.04

Top of head

8.69

atrophic rhinitis (Fig. 5, Table 5). Patients with headache in the forehead were maximum (43.4%) followed by headache at more than one site (34.7%) and then glabella

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Figure 8. Patients who underwent FESS due to causes other than contact points.

(13.04%) and top of head (8.69%) (Fig. 6, Table 6). About 35.08% of patients who underwent antral washout for headache and facial pain were relieved, whereas 64.92% were not relieved (Fig. 7, Table 7). About 43.47% of the patients who underwent DNE for headache had mucosal contact points as the main pathology (Fig. 8, Table 8). Out of 30 patients diagnosed as having mucosal contact points, 25 underwent FESS.

ENT Table 8. Patients Who Underwent DNE (n = 69) No. of cases

Percentage (%)

Mucosal contact points present

43.47

Mucosal contact points absent

56.52

Table 9. Patients Who Underwent FESS due to Mucosal Contact Point (n = 25) No. of cases

Percentage (%)

Total relief from headache

80.00

Significant relief

20.00

Table 10. Patients Who Underwent FESS due to Causes Other than Contact Points (n = 30) No. of cases

Percentage (%)

Completely free of pain

30.00

Significant symptom improvement

36.6

No benefit from surgery

33.3

Eighty percent of the patients who underwent FESS for headache due to mucosal contact points had complete relief from headache and 20% had significant relief (Table 9). Out of 39 patients of headache due to causes other than contact point, 30 underwent FESS. Patients who underwent FESS for causes other than mucosal contact points showed 67% improvement in headache and facial pain (Table 10). DISCUSSION According to our study, the majority of the cases of headache due to rhinogenic causes were males (54%) in the age group of 11-30 years. Similar findings were observed in the study conducted by Kumar et al (2000) wherein majority of patients of headache belonged to age group 10-30 years and 53% were males.5 Similarly, in a different study by Wenig et al6 and need Lebovics et al demonstrated a male predominance of headache due to acute frontal sinusitis in both adults and adolescents. While majority of our patients of headache due to rhinogenic causes had either DNS, acute sinusitis or osteomeatal complex disease, we also encountered patients having nasal polyps (6 patients) allergic rhinitis (4 patients) presenting with headache. Similarly, in the study by de Freitas et al, the patients of polyps along with nasal obstruction also

had facial discomfort and headache7 and according to a study conducted by Wolf, 20% of allergy patients presented with headache.8 In our study, out of 69 patients of headache due to rhinogenic causes, 30 (43.4%) patients had headache at forehead, 24 (34.7%) patients had headache at more than one site, nine (13.04%) patients had headache at glabella and six (8.69%) patients had headache at top of head. In a study conducted by Kumar et al (2000), localization of headache to forehead was 43% while headache at more than one site was seen in 19%, pain at glabella in 12% and at top of head in 9%.5 Thus, it can be concluded that headache is localized at forehead in majority of cases. We also did antral washouts in our patients of headache but only 35% of the patients were relieved. We also did DNE on 69 patients out of which 30 (43%) patients had mucosal contact points. Patients due to mucosal contact points were advised to undergo FESS. Out of 30 patients, 25 patients underwent surgery. Postoperatively, 20 patients (80%) had total relief from headache, five patients (20%) had significant relief. Various other studies in literature show similar the same results. In a study conducted by Behin et al, 23 patients underwent surgical intervention to relieve the contact points. Eighty-three percent of patients no longer complained of headache. Eight had significant relief.9 In a study conducted by Parsons et al on 34 patients who underwent surgery for contact points, a reduction in intensity was reported in 91% of patients and reduction in frequency of headache in 85% of patients postoperatively 35 (5).10 Thus, from our study and the above mentioned studies, it is clear that majority of the patients who underwent FESS for mucosal contact points were totally relieved of their symptoms. The remaining 39 patients who had pathologies other than mucosal contact points i.e., DNS, osteomeatal complex disease were also advised FESS to get rid of headache. Out of the 30 patients who underwent surgery, postoperatively, nine (30%) patients were completely free of pain, 11 (36.6%) patients had significant symptom improvement and 10 (33.3%) patients had no benefit from surgery. Thus, it showed 67% improvement and correlates with studies mentioned below: Welge-Leussen et al conducted a 10-year follow-up of patients who had undergone FESS. Out of 20 patients, six (30%) patients remained completely free of pain, seven (35%) had significant improvement and seven (35%) received no benefit from surgery (65% improvement).11

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ENT In a study conducted in Dept. of Otolaryngology, Vajira Hospital, Bangkok, Thailand, 16 patients were operated on by FESS. Their principal complaint was facial pain or headache. Ten patients had no headache postoperatively (62.5%) and six patients (37.5%) had a reduction in severity.12

ÂÂ

Headache can occur at any age. But, the highest incidence was noted in the age group 21-30 years followed by 11-20 years.

ÂÂ

Sex incidence is slightly more in males (53.62%).

ÂÂ

In patients of headache due to sinogenic cause, 20 patients (28.9%) had acute sinusitis, 20 patients (28.9%) had DNS, 17 patients (24.63%) had osteomeatal complex disease, six patients (8.69%) had polyps, four patients (5.79%) had allergic rhinitis and two (2.89%) had atrophic rhinitis.

ÂÂ

Headache was localized to forehead in 30 patients (43.4%) and more than one site in 24 patients (34.7%), at the glabella in nine patients (13.04%) and at the top of head in six patients (8.69%).

ÂÂ

Out of 69 patients of headache due to sinogenic causes, 57 underwent antral washout, 20 patients were relieved of their headache and facial pain (35.08%) and 37 patients (64.9%) were not relieved.

ÂÂ

All the 69 patients underwent DNE out of which 30 patients (43.47%) were found to have mucosal contact points.

ÂÂ

Out of 30 patients of headache due to mucosal contact points, 25 underwent FESS; of these, 20 patients (80%) had total relief from headache and five patients (20%) had significant relief.

ÂÂ

Out of the remaining 39 patients of headache, 30 patients underwent FESS, nine patients (30%) had complete relief from pain, 11 patients (36.6%) had significant symptom improvement, 10 patients (33.3%) had no benefit from surgery. This showed that 67% of patients had improvement of headache after undergoing FESS.

ÂÂ

Endoscopic management of headache due to sinogenic causes provides a tool to the surgeon by which he can accurately diagnose meticulously and with minimal trauma operate and precisely provide postoperative care and follow-up.

ÂÂ

The use of microdebrider provides an excellent surgical result with fewer complications and faster healing than traditional techniques in FESS.

Thus, from the present study and the above mentioned studies, an improvement in headache in 63-67% of patients operated should be expected after the patients undergo FESS for headache. CONCLUSION Sinusitis refers to a group of disorders characterized by inflammation of the mucosa of the PNS. Now-adays rhinosinusitis is the preferred term to describe the inflammation of the nose and PNS. Headache is nearly a universal human experience. The lifetime incidence of headache is estimated to be at least 90%. Before treating the headache it should be known if the headache is primary (when no clear pathologic condition can be identified) or secondary (metabolic, infectious, inflammatory, traumatic, neoplastic, immunologic, endocrine, vascular). To know whether the headache is sinogenic or not, firstly the patient is assessed clinically, then radiological investigations (X-ray PNS) are done. Patients also undergo DNE. Medical line of treatment with antibiotics, antihistamines, anti-inflammatories, nasal decongestants will be beneficial only in acute cases of sinusitis without any anatomical variation. Most cases of sinusitis presenting with headache are acute cases or acute-on-chronic sinusitis. Antral lavage can be a relief from headache for some patients. Role of FESS is huge when no obvious clinical abnormality is made out and ultimately it is FESS that is the cure for headache due to rhinogenic causes. Now-a-days suction irrigation endoscopy should be used for visual control during surgery. Microdebrider should be used for FESS as it provides atraumatic dissection with minimum bleeding, which enables decreased surgical time and faster postoperative healing. SUMMARY ÂÂ

A total of 100 patients presenting with headache to Dept. of ENT were recruited for the study.

ÂÂ

Out of 100 patients, 69 patients had headache due to sinogenic causes.

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REFERENCES 1. Cady RK, Schreiber CP. Sinus headache: a clinical conundrum. Otolaryngol Clin North Am 2004;37(2):267-88. 2. Michaels B. Rhinosinusitis. Scott-Brown’s Otorhinolaryngology HNS. 7th edition, p.1439-48. 3. Seiden AM, Martin VT. Headache and the frontal sinus. Otolaryngol Clin North Am 2001;34(1):227-41. 4. Stammberger H. Functional Endoscopic Sinus Surgery: The Messerklinger Technique. Mosby-Year Book: St. Louis 1991:p.70-6.

ENT 5. Kumar P, Chawla P. A correlative study of sinusitis versus headache. Indian J Otolaryngol Head Neck Surg 2000;52(2):125-7. 6. Wenig BL, Goldstein MN, Abramson AL. Frontal sinusitis and its intracranial complications. Int J Pediatr Otorhinolaryngol 1983;5(3):285-302.

9. Behin F, Behin B, Behin D, Baredes S. Surgical management of contact point headaches. Headache 2005;45(3):204-10. 10. Parsons DS, Batra PS. Functional endoscopic sinus surgical outcomes for contact point headaches. Laryngoscope 1998;108(5):696-702.

7. Freitas MR, Giesta RP, Pinheiro SD, Silva VC. Antrochoanal polyp: a review of sixteen cases. Rev Brasi Otolaryngol 2006;72(6):831-5.

11. Welge-Luessen A, Hauser R, Schmid N, Kappos L, Probst R. Endonasal surgery for contact point headaches: a 10-year longitudinal study. Laryngoscope 2003;113(12):2151-6.

8. Donald J, Dalessio. Allergy, atopy, nasal diseases and headache, Wolf’s Headache and other Head Pain. 5th edition.

12. Boonchoo R. Functional endoscopic sinus surgery in patients with sinugenic headache. J Med Assoc Thai 1997;80(8):521-6.

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Breastfeeding Tied to Fewer Ear, Sinus Infections in Children NEW YORK (Reuters Health) - Breastfeeding is known to help ward off infections among infants, but a new US study suggests that protection may be much longer lasting. Among thousands of 6 year olds followed from birth, those who were breastfed as babies were far less likely to have ear, sinus or throat infections later in childhood. And the longer the children were breastfed during their first year, the lower their odds of those infections at age 6. “This study provides hard evidence that health benefits of breastfeeding go beyond infancy and breastfeeding seems to be the best prescription for preventing these infections,” said Dr Ruowei Li, an epidemiologist at the Centers for Disease Control and Prevention (CDC) in Atlanta, who led the study.

CVS Test Enhances Illness Awareness in Patients with Schizophrenia Caloric vestibular stimulation (CVS), a test commonly used by ENT specialists and audiologists to test patients’ balance, could transiently enhance illness awareness in patients with schizophrenia, reports a pilot proof-ofconcept study presented at the American Society of Clinical Psychopharmacology (ASCP) 2014 Annual Meeting.

Neck Surgery Unnecessary for Many Throat Cancer Patients Study shows that among those whose cancer was triggered by a virus, any lingering bumps after chemotherapy and radiation tend to be benign. A new study shows that patients with human papillomavirus (HPV) - the same virus associated with both cervical and head and neck cancer - positive oropharyngeal cancer see significantly higher rates of complete response on a post-radiation neck dissection than those with HPV-negative oropharyngeal cancer. Fox Chase Cancer Center researchers presented the findings at the American Society for Radiation Oncology’s 56th Annual Meeting. “For patients that achieve a complete response, neck surgery is probably unnecessary,” says Thomas J. Galloway, MD, Attending Physician and Director of Clinical Research at Fox Chase and lead author on the study. Interestingly, patients with HPV often respond better to treatment for their oropharyngeal tumors than those without. The researchers noted the same trend here - people who tested positive for HPV (measured by the presence of a protein called p16) were less likely to have a recurrence of their cancers, regardless of whether or not the tumors had completely disappeared following treatment. Indeed, patients’ HPV status was the strongest predictor of whether or not they were alive at the end of the study.

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Diagnosis and Management of Chronic Cough due to Extrapulmonary Etiologies KN Mohan Rao

Abstract Cough remains one of the chief complaints for which patients seek medical attention. It has been estimated that at least 25% of chronic cough cases are caused by multiple, simultaneous causes. Cough is also an important presenting feature of a number of extrapulmonary conditions, such as cardiac diseases, upper airway diseases, gastroesophageal reflux diseases and neurological/ psychological conditions. The diagnosis of extrapulmonary causes of cough is quite challenging and the management is complicated by poor treatment response if underlying etiological mechanisms are overlooked. The intention of this article is to highlight the importance and consequences of nonpulmonary etiologies of cough such as drug-induced vocal cord dysfunction, gastroesophageal reflux disease, laryngeal reflux and neuropathic disorders and to discuss about management strategies for each etiology.

Keywords: Chronic cough, extrapulmonary causes, mechanisms, management options

ough is a vital physiological reflex, which protects the airways from entry of harmful substances.1,2 Acute cough (<3 weeks), generally presents as a brief, benign and self-limiting condition3,4 while chronic cough (>8 weeks) may be a key symptom of several chronic respiratory conditions.4 Multiple aggravates have been linked to the pathogenesis of cough and it has been estimated that in at least 25% of chronic cough cases, cough is due to the presence of multiple, simultaneous causes.4,5 Apart from respiratory causes, cough is also an important presenting feature of a number of extrapulmonary conditions, such as those involving upper airways, cardiac, neurological/ psychological diseases and gastroesophageal reflux disease (GERD).4,6,7 In a study involving 1,332 patients with chronic persistent cough who attended a chest clinic, nonpulmonary causes such as rhinosinusitis and gastroesophageal reflux were found to contribute to 60% and 9% of cases, respectively.8 Additionally, patients with chronic cough also present with an array of sensory symptoms associated with laryngeal neural dysfunction.9 Diagnosing cough due to extrapulmonary cases can present as an intimidating challenge to physicians since cough can arise from practically anywhere the

vagus nerve travels.10 Analogous to the chronic pain syndrome both peripheral and central sensitizations are implicated in chronic cough; and cough due to extrapulmonary sites such as the esophagus has been linked to visceral hypersensitivity occurring as a result of central sensitization.11 Difficult-to-treat cough is often considered to be functional or psychogenic, often overlooking extrapulmonary causes of cough such as GERD and this can lead to treatment failure with available agents.12 Uncontrolled chronic cough can considerably affect patientsâ&#x20AC;&#x2122; quality-of-life and precipitate anxiety, physical distress and social and personal discomfiture.13 The objective of this article is to highlight the importance and consequences of extrapulmonary etiologies of cough. This article also addresses the effective diagnosis and management of cough induced by drugs, vocal cord dysfunction (VCD), GERD, laryngeal reflux, cardiac diseases and neurological disorders. In preparing this article, PUBMED was searched for studies/guidelines published in the English language using the MeSH terms: Cough, causes of cough, etiology of cough, nonpulmonary causes and extrapulmonary causes of cough. Common Extrapulmonary Causes of Chronic Cough

Professor and Head Dept. of Chest Disease Raja Rajeswari Medical College and Hospital, Bangalore E-mail: kotnur.rao@gmail.com

In the vast majority of patients, airway disorders such as asthma, nonasthmatic eosinophilic bronchitis, bronchiectasis, atopic cough, chronic bronchitis,

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INTERNAL MEDICINE Table 1. Extrapulmonary Causes of Chronic Cough6,13 Drugs Angiotensin-converting enzyme inhibitors and β-blockers Upper airway diseases Postnasal drip syndrome, vocal cord dysfunction, obstructive sleep apnea Esophageal causes Gastroesophageal reflux disease, laryngopharyngeal reflux and tracheoesophageal fistula Cardiac diseases Chronic heart failure, pulmonary congestion and endocarditis, etc. Neurological/psychological causes Psychogenic (habit) cough

sarcoidosis, aspiration and airway foreign bodies as well as benign and malignant tumors involving the airways and parenchyma are considered as the common etiological factors for chronic cough.13 However, the importance of extrapulmonary causes of cough cannot be disregarded and these causes have been listed in Table 1.6,13 Chronic Cough due to Various Extrapulmonary Etiologies

Drug-induced Cough Drugs, as a cause of a myriad of pulmonary diseases, have been in focus for many years. Contrary to a review published in 1972, which has reported that 19 drugs have the potential to cause pulmonary diseases, recent estimates have indicated that more than 350 drugs have the potential role in causing pulmonary diseases including chronic cough.14 Drugs are being increasingly recognized as a cause of chronic cough particularly drugs belonging to the angiotensin-converting enzyme (ACE) inhibitor class. Between 5% and 35% of people suffer from chronic nocturnal cough with the use of ACE inhibitors (ACEIs). The mechanism is thought to be through the release of bradykinin by ACEIs, which is otherwise metabolized by ACE in the lungs. This results in a characteristic tickling, scratchy or itchy sensations in the throat.15 Beta-blockers are also known to produce cough, which may be an initial manifestation of drug-related airway hyper-responsiveness or bronchoconstriction. Apart from cough, wheeze and dyspnea may occur with the use of β-blockers. Calcium channel antagonists

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are known to induce reflux cough by relaxing the lower esophageal sphincter pressure and also by a dose-dependent impairment of esophageal clearance. Bronchoconstriction has been observed with the use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) in 5% of people with asthma. This could be due to the production of cysteinyl leukotriene and inhibition of cyclooxygenase-1 enzyme.15 Clinical, radiological and histological findings are generally nonspecific and make the diagnosis of druginduced cough difficult. A careful consideration of drug history and ruling out other causes of cough can help in diagnosing drug-induced cough. Management includes discontinuation of the relevant drug that is implicated to produce cough.14

Upper Airway Diseases and Cough Postnasal Drip Syndrome Postnasal drip is part of upper airway cough syndrome, which includes rhinitis and rhinosinusitis. It is generally associated with chronic cough and patients typically present with symptoms such as frequent throat clearing, hoarseness, nasal congestion and sensation of dripping at the back of throat.1 Therapy with proton pump inhibitors may also be beneficial in patients with postnasal drip syndrome apart from regular medications such as antihistamines, nasal steroids and decongestants.13 Vocal Cord Dysfunction Vocal cord dysfunction is characterized by periodic involuntary paradoxical adduction of the vocal cords, which can lead to acute severe dyspnea that is nonresponsive to conventional asthma therapy.16 Females have a higher preponderance to develop VCD compared to males with an estimated incidence of 40:1.17 There are three presentations of VCD as follows:17 ÂÂ

Exercise-induced VCD: The symptoms are linked to exercise.

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Spontaneous VCD: Indicates a sudden onset of symptoms without exercise.

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Persistent VCD: Indicates adduction of vocal cords during both inspiration and expiration.

Apart from exercise, certain other triggers are implicated for VCD, such as psychological conditions, airborne irritants, rhinosinusitis, GERD or use of certain drugs. Cough is one of the characteristic features observed in patients with VCD, which presents with recurrent episodes of subjective respiratory distress. Diagnosis

INTERNAL MEDICINE of VCD can be made with pulmonary function testing with a flow-volume loop and flexible laryngoscopy.18 In acute cases, reassurance and breathing instructions can relieve VCD; however, in the long-term, elimination of precipitating factors may be useful. Evidence suggests that a number of patients with VCD, which is commonly diagnosed as a mimic of asthma, receive overtreatment with inhaled corticosteroids and consequently have considerable adverse effects. Hence, appropriate diagnosis and management of VCD is crucial to avoid iatrogenic complications.16 Apart from these upper airway diseases, patients with sleep apnea also complain of chronic cough.6

Gastroesophageal Reflux Disease Chronic cough is a prominent feature in GERD and is the sole symptom in up to 75% of cases. In adults with microaspiration, cough follows symptoms of heartburn, regurgitation, sour taste, dysphonia, hoarseness and throat pain.19 GERD has also been implicated in several other pulmonary diseases, such as bronchial asthma, chronic bronchitis and diffuse pulmonary fibrosis that have cough as a presenting symptom. In more than 90% of patients with chronic persistent cough, GERD, bronchial asthma and postnasal drip syndrome either alone or in combination has been implicated as a causative factor. The principal mechanisms of cough caused by GERD include aspiration of gastric contents, autonomic dysfunction and vagally-mediated distal esophagealtracheobronchial reflexes. A self-perpetuating positive feedback cycle between cough and esophageal reflux has been proposed recently whereby cough originating from any cause may precipitate further reflux, which may worsen the cough (see Fig. 1).20

Cough

Increased transient lower esophageal sphincter relaxation and transdiaphragmatic pressure

Proton pump inhibitors

The following features help in predicting chronic cough due to GERD:21 ÂÂ

Complaints of a dry or productive cough for a period of at least 2 months

ÂÂ

Cough observed in nonsmokers and those not exposed to other environmental irritants

ÂÂ

Cough in individuals not taking an ACEI

ÂÂ

A normal or near-normal chest radiograph

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No evidence of symptomatic asthma or cough not improving with asthma medications

ÂÂ

No evidence of postnasal drip syndrome due to rhinosinusitis and the use of first-generation H1antagonists have failed to improve cough

ÂÂ

No evidence of eosinophilic bronchitis as confirmed by negative sputum studies or cough not improving with inhaled/systemic corticosteroids.

Empirical medical antireflux therapy with proton pump inhibitors may be useful in managing patients with GERD and cough but there is a significant failure rate associated with this in which case antireflux surgery may be useful.20

Laryngopharyngeal Reflux Chronic laryngitis occurs as a result of exposure to irritants. However, reflux-induced laryngitis or laryngopharyngeal reflux (LPR) may be observed in patients not exposed to irritants.22 The differentiating features between GERD and LPR are described in Figure 2.21 Laryngoscopy and 24-hour pH monitoring are the most common tests used for the diagnosis of reflux-related laryngitis.23 In a study by Patterson et al involving 19 patients with asthma and 18 patients with chronic cough, nonacid reflux episodes reaching the pharynx was found to be an important factor associated with cough that was assessed using multi-channel intraluminal impedance and pH monitoring in the esophagus and hypopharynx.24 Use of acid suppressive drugs have produced insufficient treatment response in patients with LPR.23

Distal esophageal and tracheobronchial reflux

GERD

Figure 1. Positive feedback cycle between cough and esophageal reflux.

Gastroesophageal reflux

Laryngopharyngeal reflux

yy Heartburn yy Acid reflux symptom yy Aggravated at night and when lying down

yy Dry cough yy Voice change, throat clearing yy Aggravated when eating, standing

Figure 2. Differentiating features between GERD and LPR.21

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INTERNAL MEDICINE Cardiac Causes Cough is one of the presenting features of heart failure with pulmonary congestion; therefore, a high index of suspicion for left ventricular heart failure should be maintained by the physicians in patients presenting with a new or worsening cough.22 Dry irritating cough, particularly nocturnal, is observed in patients with chronic heart failure and it is often mistaken for asthma, bronchitis or ACEI-induced cough.25 Nonproductive cough with shortness of breath may be observed in patients with acute pericarditis.26 Cough can also arise as a side-effect of medications used for the treatment of cardiac conditions, such as ACEIs, Î˛-blockers and amiodarone. Therefore, a targeted diagnostic and

treatment approach should be undertaken for relieving cough in such patients.6

Neurological/Psychological Causes Cough due to Neuromuscular Causes Coughing and choking are frightening and distressing symptoms observed in patients with neuromuscular diseases and are generally a consequence of a need to cough but with impaired efficacy of the cough reflex. Coughing is precipitated by a variety of factors in patients with upper and lower motor neuron dysfunction who suffer from varying degrees of respiratory muscle weakness, dysphagia and laryngeal

Cough lasting more than 8 weeks History and physical examination Normal chest radiography findings

History of cough due to use of drug (angiotensinconverting enzyme inhibitor)

yy Heartburn, respiratory symptoms, water brash, regurgitation yy Symptoms worse when lying down yy Positive results of pH

yy Dry cough yy Voice change yy Frequent throat clearing

yy Upper respiratory tract signs and symptoms yy Cough worsened by allergens, temperature changes or pregnancy indicates rhinitis

Frequent involuntary paradoxical adduction of the vocal cords, and acute severe dyspnea

Cough related to cardiac diseases

Repeated throat clearing with no other cause of cough

GERD

Reflux-related laryngitis

Postnasal drip

Vocal cord dysfunction

Targeted diagnosis and treatment

Others (habit/ psychogenic cough)

Acid suppressant drug (?)

yy First-generation antihistamine, ipratropium bromide and nasal steroids yy Surgery for severe, recalcitrant cases

yy Reassurance and breathing instructions (short-term) yy Eliminating aggravating factors (long-term)

Drug-induced

Discontinue the relevant drug OR Adjust dose of angiotensinconverting enzyme inhibitor OR Consider using an angiotensinIIâ&#x20AC;&#x201C;receptor inhibitor

Conservative options yy Weight loss yy Avoid exacerbating foods yy Smoking cessation Drugs yy H2 antagonists for 6 months yy Re-evaluate with pH probe and endoscopy yy Proton pump inhibitor yy Fundoplication for severe, recalcitrant cases

Figure 3. Algorithm for managing chronic cough due to extrapulmonary causes.16,19,29

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Specific therapy (behavior modification or psychiatric intervention)

INTERNAL MEDICINE dysfunction.27 In a small case series, cough was observed to be a presenting feature in patients with mononeuritis multiplex, diabetic autonomic neuropathy, HolmesAdie syndrome and hereditary sensory neuropathy 1.28 Habit or Psychogenic Cough Habit cough or psychogenic cough is associated with a throat clearing noise. The 2006 American College of Chest Physicians evidence-based clinical practice guidelines state that the diagnosis of habit cough can be made only after an extensive evaluation is undertaken to rule out tic disorders and uncommon causes of cough. This type of cough improves with specific therapy, which includes behavior modification or psychiatric intervention.29 General Principles in the Management of Chronic Cough Associated with Extrapulmonary Diseases

Evaluation and History Taking Patient evaluation and history taking are an important part of initial evaluation of patients presenting with cough caused by extrapulmonary factors. The nature, frequency, onset, duration, medication use and aggravating factors of chronic cough should be determined by proper history taking. In addition, details of response to previous treatment can also be derived from initial assessments.21

Diagnosis and Management Chest radiography forms an important initial investigation to help detect several ominous pulmonary diseases that may need specialist care. When results of chest radiographs are normal, pulmonary (asthma and postnasal drip), as well as extrapulmonary causes of cough such as drug-induced, GERD or postinfectious are probable etiologies. Specific treatment measures have been described in Figure 3.16,19,29 In some instances, additional investigations including methacholine challenge test, sinus radiography and an esophageal pH probe are needed to confirm the diagnosis. Antitussive Treatment Treatment directed against aggravating factors of chronic cough often remains suboptimal; therefore, antitussive therapies are sometimes needed for symptomatic relief.30 Antitussives can be categorized as centrally or peripherally acting.31 Centrally acting antitussive agents have been used as antitussive agents of choice for decades and include codeine,

dextromethorphan, methadone and morphine.31,32 These agents inhibit cough primarily by their effect on the cough center in the brain.31 Most antitussives are combinations of dextromethorphan or codeine with antihistamines, expectorants, decongestants and/or antipyretics.33 These antitussives are useful in the symptomatic relief of dry or nonproductive cough. Codeine is one of the most commonly preferred centrally acting cough suppressants. Findings from a meta-analysis which included five studies on efficacy of dextromethorphan and codeine in adults with cough concluded that central antitussives have marginally superior efficacy when compared to placebo.31 Conclusion Chronic cough remains one of the most common complaints for which patients seek medical help. Chronic cough has a significant impact on patientsâ&#x20AC;&#x2122; quality-of-life and causes considerable social and psychological distress. Cough is not only a symptom of respiratory conditions but is also a key indicator of nonpulmonary pathologies such as gastroesophageal disease, infections, VCD, LPR, cardiac and neurological diseases. Management options for extrapulmonary cough are specific and directed towards managing the aggravating factors. However, the response to specific treatments for these conditions is unpredictable and there is a high incidence of treatment failure prompting the need for use of antitussives in such instances. Centrally acting antitussive agents such as codeine and dextromethorphan may have a role in the symptomatic relief of dry or nonproductive cough. References 1. Singh N, Singh V. Combating cough - etiopathogenesis. J Assoc Physicians India 2013;61(5 Suppl):6-7. 2. Chung KF, Pavord ID. Prevalence, pathogenesis, and causes of chronic cough. Lancet 2008;371(9621):1364-74. 3. Morice AH. Epidemiology of cough. Pulm Pharmacol Ther 2002;15(3):253-9. 4. Morice AH, McGarvey L, Pavord I; British Thoracic Society Cough Guideline Group. Recommendations for the management of cough in adults. Thorax 2006;61 Suppl 1:i1-24. 5. Madison JM, Irwin RS. Cough: a worldwide problem. Otolaryngol Clin North Am 2010;43(1):1-13. 6. Kardos P. Management of cough in adults. Breathe 2010;7(2):122-33. 7. Albert NM, Davis M, Young J. Improving the care of patients dying of heart failure. Cleve Clin J Med 2002;69(4):321-8.

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INTERNAL MEDICINE 8. Al-Mobeireek AF, Al-Sarhani A, Al-Amri S, Bamgboye E, Ahmed SS. Chronic cough at a non-teaching hospital: Are extrapulmonary causes overlooked? Respirology 2002;7(2):141-6. 9. Chung KF, McGarvey L, Mazzone SB. Chronic cough as a neuropathic disorder. Lancet Respir Med 2013;1(5):414-22. 10. Simpson CB, Amin MR. Chronic cough: state-of-the-art review. Otolaryngol Head Neck Surg 2006;134(4):693-700. 11. Woodcock A, Young EC, Smith JA. New insights in cough. Br Med Bull 2010;96:61-73. 12. Jeyakumar A, Brickman TM, Haben M. Effectiveness of amitriptyline versus cough suppressants in the treatment of chronic cough resulting from postviral vagal neuropathy. Laryngoscope 2006;116(12):2108-12. 13. Iyer VN, Lim KG. Chronic cough: an update. Mayo Clin Proc 2013;88(10):1115-26. 14. Verma S, Mahajan V. Drug induced pulmonary diseases. Int J Pulmon Med 2007;9:2. 15. Medford AR. A 54 year-old man with a chronic cough Chronic cough: don’t forget drug-induced causes. Prim Care Respir J 2012;21(3):347-8. 16. Kenn K, Balkissoon R. Vocal cord dysfunction: what do we know? Eur Respir J 2011;37(1):194-200. 17. Varney V, Parnell H, Evans J, Cooke N, Lloyd J, Bolton J. The successful treatment of vocal cord dysfunction with low-dose amitriptyline - including literature review. J Asthma Allergy 2009;2:105-10. 18. Deckert J, Deckert L. Vocal cord dysfunction. Am Fam Physician 2010;81(2):156-9. 19. D’Urzo A, Jugovic P. Chronic cough. Three most common causes. Can Fam Physician 2002;48:1311-6. 20. Ing AJ. Cough and gastro-oesophageal reflux disease. Pulm Pharmacol Ther 2004;17(6):403-13. 21. Jeong JW. The causes of chronic cough: Chronic cough due to extrapulmonary etiologies. Korean J Med 2010;78(6):670-3.

22. W est LM. Causes of cough. J Malta Coll Pharm Pract 2010;16:23-6. 23. Moore JM, Vaezi MF. Extraesophageal manifestations of gastroesophageal reflux disease: real or imagined? Curr Opin Gastroenterol 2010;26(4):389-94. 24. Patterson N, Mainie I, Rafferty G, McGarvey L, Heaney L, Tutuian R, et al. Nonacid reflux episodes reaching the pharynx are important factors associated with cough. J Clin Gastroenterol 2009;43(5):414-9. 25. Guidelines for the prevention, detection and management of chronic heart failure in Australia. Updated Oct. 2011. National Heart Foundation of Australia. 26. Maisch B. Guidelines on the diagnosis and management of pericardial diseases. The Task Force on the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology. Eur Heart J 2004;1:1-28. 27. Hadjikoutis S, Wiles CM, Eccles R. Cough in motor neuron disease: a review of mechanisms. QJM 1999;92(9): 487-94. 28. Karur PS, Morjaria JB, Wright C, Morice AH. Neurological conditions presenting as airway reflux cough. Eur Respir Rev 2012;21(125):257-9. 29. Irwin RS, Glomb WB, Chang AB. Habit cough, tic cough, and psychogenic cough in adult and pediatric populations: ACCP evidence-based clinical practice guidelines. Chest 2006;129(1 Suppl):174S-179S. 30. Pavord ID, Chung KF. Chronic Cough 2: Management of chronic cough. Lancet 2008;371:1375-84. 31. De Blasio F, Virchow JC, Polverino M, Zanasi A, Behrakis PK, Kilinç G, et al. Cough management: a practical approach. Cough 2011;7(1):7. 32. Reynolds SM, Mackenzie AJ, Spina D, Page CP. The pharmacology of cough. Trends Pharmacol Sci 2004;25(11):569-76. 33. Padma L. Current drugs for the treatment of dry cough. J Assoc Physicians India 2013;61(5 Suppl):9-13.

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INTERNAL MEDICINE

Acute Onset Hypokalemic Quadriparesis with Dengue Fever: A Case Report Praveen kumar*, Kalpana Chandra†, Amit Varshney‡

Abstract Dengue fever is an acute viral disease caused by dengue virus (DENV1- 4) and is endemic to India. It commonly presents as fever along with headache, bodyache, rashes, polyserositis, bleeding manifestations and rarely as cardiovascular, gastrointestinal, renal or neurological manifestations. Here, we report a case of dengue fever with hypokalemic quadriparesis. A 38-year-old male admitted with history of fever of 3-day duration and weakness of all four limbs of 1-day duration. His investigations showed Hb - 16.20 g/dL, platelet - 37,000/mm3, serum Na+ - 150.00 mmol/L, serum K+ - 2.50 mmol/L and positive dengue serology. Hypokalemic quadriparesis secondary to dengue fever should be considered as a differential diagnosis in a case of acute febrile illness with muscle weakness in tropical countries.

Keywords: Dengue fever, hypokalemia, hypokalemic paralysis

engue fever is an acute viral disease caused by dengue virus (DENV 1-4) and occurs epidemically and endemically in tropical countries, commonly during rainy season. Dengue infection present as classic dengue fever, dengue hemorrhagic fever or dengue shock syndrome characterized by fever along with headache, bodyache, rashes, polyserositis and bleeding manifestation.1

There are reports of neurological involvement in the form of encephalopathy/encephalitis, Guillain-Barre syndrome (GBS), cerebrovascular accident (CVA) and transverse myelitis.1,2 Here, we report a case of acute hypokalemic quadriparesis secondary to dengue infection. CASE Report A 38-year-old male was admitted with history of weakness of all four limbs of 1-day duration. Patient was apparently well 3 days back when he developed

*Associate Professor Dept. of Medicine †Associate Professor Dept. of Pathology ‡Resident Dept. of Medicine Shri Ram Murti Smark Institute of Medical Sciences, Bhojipura, Bareilly, Uttar Pradesh Address for correspondence Dr Praveen Kumar A-1, Doctor’s Residence Shri Ram Murti Smark Institute of Medical Sciences, Bhojipura, Bareilly, Uttar Pradesh - 243 202 E-mail: praveen_kmr_23@yahoo.co.in

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fever, which was high-grade and persisted for 1 day. On second day, he developed sudden onset weakness, which started in lower limbs and progressed to all four limbs in 24 hours. On examination, he was afebrile with pulse of 54/min and blood pressure (BP) 130/80 mmHg. His neurological examination revealed normal mental function, cranial nerves and sensory system. His power was 2/5 in lower limbs and 4/5 in upper limbs with normal nutrition, tone and reflexes. Other systems such as cardiovascular system (CVS), respiratory system (RS) and per abdominal (PA) were within normal limits. His investigations on the date of admission revealed total leukocyte count (TLC) 10,100/mm3, differential leukocyte count (DLC) N90%L10%M0%E0%, erythrocyte sedimentation rate (ESR) 04 mm/1st hour, packed cell volume (PCV) - 44%, blood sugar random (BSR) - 161.00 mg/dL, serum urea 31.00 mg/dL, serum creatinine - 0.80 mg/dL, serum bilirubin (total) - 1.30 mg/dL, serum bilirubin (direct) 0.70 mg/dL, serum bilirubin (indirect) - 0.60 mg/dL, serum glutamic oxaloacetic transaminase (SGOT) 303.00 IU/L, serum glutamic pyruvic transaminase (SGPT) - 159.00 IU/L, serum T3 - 1.0 ng/mL (N), T4 - 6-5 ug/dL (N) and thyroid-stimulating hormone (TSH) 2.9 U IU/mL (N). His hemoglobin (Hb), platelet, sodium and potassium were monitored and were as shown in Table 1. Dengue serology was done and was positive (immunoglobulin M [IgM]-positive [28.80 units], immunoglobulin G (IgG)-positive [28.80 units]).

INTERNAL MEDICINE Table 1. Hemoglobin Levels, Platelet Count, Sodium and Potassium Levels as Monitored During the Stay in the Hospital Date

Hemoglobin

Platelet

Sodium

Potassium

22/10/2013

16.20 g/dL

37,000/mm3

150.00 mmol/L

2.50 mmol/L

23/10/2013

16.50 g/dL

40,000/mm3

145.00 mmol/L

4.40 mmol/L

17.10 g/dL

37,000/mm3

25/10/2013

16.20 g/dL

37,000/mm3

26/10/2013

15.40 g/dL

66,000/mm3

141.00 mmol/L

4.80 mmol/L

28/10/2013

15.60 g/dL

1.48 lac/mm3

24/10/2013

He was diagnosed as a case of dengue fever with acute onset quadriparesis due to hypokalemia. He was given oral potassium along with other supportive care. His quadriparesis improved after 2 days of admission, whereas the platelets count normalized after 5 days of admission. DISCUSSION Dengue infection present as classic dengue fever, dengue hemorrhagic fever or dengue shock syndrome characterized by fever along with headache, bodyache, rashes, polyserositis and bleeding manifestations.1 Patient can also have atypical presentations in the form of hepatitis/fulminant hepatic failure, acalculus cholecystitis, pancreatitis, febrile diarrhea, hemolytic uremic syndrome, renal failure, myocarditis, pericarditis, conduction abnormalities, acute respiratory distress syndrome (ARDS), pulmonary hemorrhage, spontaneous splenic rupture and lymph node infarction.1 The atypical systemic manifestations are because of affection of endothelium by immunopathological mechanisms leading to increased vascular permeability and coagulation disorder.1 Patients may also have atypical neurological manifestations, which can be grouped into three categories: ÂÂ

Related to neurotrophic effect of viruses: Encephalitis, meningitis, myositis, rhabdomyolysis and myelitis

ÂÂ

Related to systemic complication of dengue infection: Encephalopathy, stroke, hypokalemic paralysis and papilledema.

ÂÂ

Post-infection: Acute disseminated encephalomyelitis, myelitis, neuromyelitis optica, optic neuritis, GBS, Miller-Fisher syndrome, phrenic neuropathy, long thoracic neuropathy, oculomotor palsy, maculopathy and fatigue syndrome.3

Here we are reporting a case of dengue fever with hypokalemic quadriparesis, which is characterized

clinically by hypokalemia and acute systemic weakness. Hypokalemia in association with infectious diseases have been reported and documented in up to 28% cases.4 Mishra et al conducted a study on 17 patients of dengue fever, six were having acute motor weakness.2 Koshy et al conducted a study on 799 patients of dengue fever. Out of 799, 21 (2.63%) were having neurological presentation including seven cases of hypokalemia with quadriparesis.5 Jha and Ansari reported three confirmed cases of dengue infection suffering from pure motor reversible quadriparesis due to hypokalemia.6 The exact cause of hypokalemic paralysis in dengue infection is not known and it may not be possible to attribute a single definite pathophysiological basis. Hypokalemia may be secondary to re-distribution of potassium into the cells, transient renal tubular abnormalities leading to increased urinary potassium wasting and or loss of potassium due to vomiting and diarrhea in febrile phase of dengue fever. The secondary re-distribution of potassium into the cell may be due to increased catecholamine levels secondary to infections and secondary insulin resistance. Endogenous granulocyte macrophagecolony stimulating factor (GM-CSF) and related cytokines in response to neutropenia may be another putative factor leading to intracellular potassium shift and hyopkalemia.6 Hyperreninemia may also be responsible for hypokalemia in dengue hemorrhagic fever/dengue shock syndrome due to hypovolemic state.7 CONCLUSION Hypokalemic quadriparesis secondary to dengue fever should be considered as a differential diagnosis in a case of acute febrile illness with muscle weakness in tropical countries like India especially in rainy season.

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

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

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

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

Who is Eligible?

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

Objectives Assist heart patients belonging to economically weaker sections of the society in getting affordable and quality treatment. Raise awareness about the fundamental right of individuals to medical treatment irrespective of their religion or economical background. Sensitize the central and state government about the need for a National Cardiovascular Disease Control Program. Encourage and involve key stakeholders such as other NGOs, private institutions and individual to help reduce the number of deaths due to heart disease in the country. To promote heart care research in India.

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

Important Notes The patient must be a citizen of India with valid Voter ID Card/ Aadhaar Card/Driving License. The patient must be needy and underprivileged, to be assessed by Fund Committee. The HCFI Fund reserves the right to accept/reject any application for financial assistance without assigning any reasons thereof. The review of applications may take 4-6 weeks. All applications are judged on merit by a Medical Advisory Board who meet every Tuesday and decide on the acceptance/rejection of applications. The HCFI Fund is not responsible for failure of treatment/death of patient during or after the treatment has been rendered to the patient at designated hospitals.

To promote and train hands-only CPR.

Activities of the Fund Financial Assistance

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

Financial assistance is given to eligible non emergent heart patients. Apart from its own resources, the fund raises money through donations, aid from individuals, organizations, professional bodies, associations and other philanthropic organizations, etc.

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

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

Drug Subsidy

The HCFI Fund has the right to print/publish/webcast/web post details of the patient including photos, and other details. (Under taking needs to be given to the HCFI Fund to publish the medical details so that more people can be benefitted). The HCFI Fund does not provide assistance for any emergent heart interventions.

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

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

BPL Card (If Card holder)

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

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

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

Free Diagnostic Facility

Free Education and Employment Facility

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

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

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

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

About Heart Care Foundation of India

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

Heart Care Foundation of India was founded in 1986 as a National Charitable Trust with the basic objective of creating awareness about all aspects of health for people from all walks of life incorporating all pathies using low-cost infotainment modules under one roof. HCFI is the only NGO in the country on whose community-based health awareness events, the Government of India has released two commemorative national stamps (Rs 1 in 1991 on Run For The Heart and Rs 6.50 in 1993 on Heart Care Festival- First Perfect Health Mela). In February 2012, Government of Rajasthan also released one Cancellation stamp for organizing the first mega health camp at Ajmer.

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

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

Committee Members

Chief Patron

President

Raghu Kataria

Dr KK Aggarwal

Entrepreneur

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

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

Advisors Mukul Rohtagi Ashok Chakradhar

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

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

Rishab Soni

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

http://heartcarefoundationfund.heartcarefoundation.org

INTERNAL MEDICINE Acknowledgment I take this opportunity to extend my gratitude and sincere thanks to all those who helped me to complete this study. I am highly thankful to Dept. of Medicine, Pathology, Biochemistry and Microbiology for providing me adequate facility, which helped me to carry out this study. I owe great sense of indebtedness to Dean SRMS-IMS, Bhojipura, Bareilly for permitting me to carry out this study.

3. Murthy JM. Neurological complication of dengue infection. Neurol India 2010;58(4):581-4. 4. Ying RS, Tang XP, Zhang FC, Cai WP, Chen YQ, Wang J, et al. Clinical characteristics of the patients with dengue fever seen from 2002 to 2006 in Guangzhou. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi 2007;21(2):123-5.

REFERENCES

5. Koshy JM, Joseph DM, John M, Mani A, Malhotra N, Abraham GM, et al. Spectrum of neurological manifestations in dengue virus infection in Northwest India. Trop Doct 2012;42(4):191-4.

1. Yeolkar ME. Dengue. In: API Textbook of Medicine. 9th edition, Volume 2, Munjal YP (Ed.), Jaypee Brothers Medical Publishers (P) Ltd. 2012:p.1158-60.

6. Jha S, Ansari MK. Dengue infection causing acute hypokalemic quadriparesis. Neurol India 2010;58(4): 592-4.

2. Misra UK, Kalita J, Syam UK, Dhole TN. Neurological manifestations of dengue virus infection. J Neurol Sci 2006;244(1-2):117-22.

7. Tuchinda C, Muarngmanee L. Plasma renin activity in children with dengue hemorrhagic fever. J Med Assoc Thai 1983;66(3):166-8.

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Biomarker to Identify Brain Injury in Concussed Athletes A research team at the Sahlgrenska University Hospital, Sweden has come up with its novel finding that blood levels of total-tau (T-tau) could serve as a potential biomarker to assess the severity of concussions in athletes and to determine when it is safe to return to play. T-tau is a protein that signals axonal damage in the brain. The study findings revealed that the plasma levels of T-tau increased in ice hockey players with sports-related concussion. The highest levels were measured immediately after the injury, and the levels declined during the first 12 hours. A second peak was noted between 12 and 36 hours. T-tau concentrations at 1 hour after concussion predicted the number of days it took for the symptoms to resolve and the players to return to play.

Risk for Death Decreased in ICU Patients with Severe Sepsis Mortality from severe sepsis decreased by 16.7% during a 12-year period in Australia and New Zealand, according to a new study by researchers in New Zealand, Australia and Finland, published online March 18 in JAMA. The study was released early in conjunction with its presentation at the International Symposium on Intensive Care and Emergency Medicine, occurring this week in Brussels, Belgium. Sepsis and septic shock account for most mortality in critically ill patients, according to background information included in the study. Although several randomized clinical trials indicate that the last 20 years have not seen much progress in improving the rates of mortality in severe sepsis, little is known about mortality trends in realworld intensive care unit (ICU) settings. Using data from the Australian and New Zealand Intensive Care Society adult ICU patient database, which includes more than 90% of all ICU admissions in Australia and New Zealand, Kirsi-Maija Kaukonen, MD, PhD, EDIC, from the Australian and New Zealand Intensive Care Research Centre, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia, and the Critical Care Research Group, Intensive Care Unit, Helsinki University Central Hospital, Finland, and colleagues looked at patients hospitalized with severe sepsis compared with all other patients in the database from January 1, 2000, to December 31, 2012. They defined severe sepsis according to the American College of Chest Physicians/Society of Critical Care Medicine criteria. Covariates included inflammatory response and organ failure, as well as admission diagnoses using Acute Physiology and Chronic Health Evaluation (APACHE) III risk for death and APACHE scores indicating infection.

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OBSTETRICS AND GYNECOLOGY

Subclinical Hypothyroidism During Pregnancy: A Clinical Review Rajat Mohanty*, Sudipta Patnaik†, Babita Ramani‡

Abstract Traditionally, overt hypothyroidism cases during pregnancy have been treated due to its adverse effect on fetus as well as on mother. Evidences are now available for the need of treatment of subclinical hypothyroidism (SCH) during pregnancy. SCH is the commonest form of hypothyroidism in pregnancy and is usually due to progressive thyroid destruction due to autoimmune thyroid disease. The prevalence and incidence of SCH is found to be more in South Asia than other parts of the world. This review revealed that screening should be mandatory followed by identification of antithyroid antibody positive cases because they require treatment with oral levothyroxine.

Keywords: Subclinical hypothyroidism, autoimmune thyroid disease, antithyroid antibody, levothyroxine

hyroid gland has an important role in brain development of fetus during pregnancy. Subclinical hypothyroidism (SCH) is the commonest form of hypothyroidism in pregnancy. SCH is present, when the thyroid-stimulating hormone (TSH) is high or normal but the thyroxine (T4) level is in the normal or low normal range. It is more predominant in South Asia. So, every pregnant women should be ruled out for SCH in first trimester. Review of Literatures

Interest in thyroid disease in pregnancy, especially SCH, has escalated in part because of reports suggesting that variously defined thyroid deficiency (including both overt and subclinical disease) during pregnancy results in impaired neurodevelopment in offspring.1,2 Further, other reports have associated SCH with preterm delivery, pre-eclampsia and postpartum thyroiditis.3,4 The prevalence of SCH could be anticipated to be between 2% and 5% of women screened, depending on the TSH and free T4 (FT4) level thresholds applied and this represents most women who would be identified with thyroid deficiency through routine screening.3

*Dept. of Obstetrics and Gynecology †Assistant Professor Dept. of Physiology SCB Medical College, Cuttack, Odisha ‡VSS Medical College, Burla, Sambalpur, Odisha Address for correspondence Dr Rajat Mohanty Plot No.: 55, Satyanagar, Bhubaneswar, Odisha - 751 007 E-mail: sudirajat@yahoo.com

These complications have led some national societies as well as public interest groups to recommend routine thyroid screening during pregnancy.5 Treatment of subclinical thyroid disorders is still controversial. This review is going to evaluate the necessity for screening of SCH during pregnancy and the diagnostic technique for confirmation. We also discuss about the requirements of treatment with levothyroxine as well as the recommendations for SCH in pregnancy provided by United State Preventive Service Task Force (USPSTF) and analyzed the gravity of the condition. Hypothyroidism is common in pregnancy with an estimated prevalence of 2-3% and 0.3-0.5% for subclinical and overt hypothyroidism, respectively in West6 and it is dependent on the TSH and FT4 level thresholds applied, and this represents most women who would be identified with thyroid deficiency through routine screening. There are a few reports of prevalence of hypothyroidism during pregnancy from India with prevalence rates ranging from 4.8% to 11%.7,8 It is also supported by some other studies.9,10 It seems that prevalence of hypothyroidism is more in Asian countries compared with the West. In a large Chinese study, which included 2,899 pregnant women, the prevalence of hypothyroidism was significantly higher in the high-risk group than in the non-high-risk group (10.9% vs 7.0%, p = 0.008).11 In North India, there is a high prevalence of hypothyroidism (14.3%), majority being subclinical in pregnant women during first trimester as shown by Dhanwal et al (2013), necessitating routine screening.12

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OBSTETRICS AND GYNECOLOGY During pregnancy, there is a transient fall in TSH in the first trimester due to the structural homology between the TSH and human chorionic gonadotropin (hCG) molecules and their receptors, allowing hCG stimulation of the thyroid with an increase in thyroid hormone production. Thyroid hormone concentrations in blood are increased in pregnancy, partly due to the high levels of hyperestrogenic state of pregnancy and due to the weak thyroid stimulating effects of hCG that acts like TSH. Action of hCG is by cross reactivity of this hormone with TSH receptors.13 T4 levels rise from about 6-12 weeks, and peak by mid-gestation but at the same time the TSH level start decreasing.14 During pregnancy, the thyroid gland may enlarge by 10% in countries where iodine sources are sufficient, and to a greater extent in iodine-poor countries.15 Production of thyroid hormones and iodine requirement each increases by approximately 50% during pregnancy.16 Gestation specific reference ranges for thyroid function tests are not widely in use although many centers are now preparing them.17,18 Fetal T4 is wholly obtained from maternal sources in early pregnancy since the fetal thyroid gland only becomes functional in the second trimester of gestation. As T4 is essential for fetal neurodevelopment it is critical that maternal delivery of T4 to the fetus is ensured early in gestation. In pregnancy, iodide losses through the urine and the fetoplacental unit contribute to a state of relative iodine deficiency.19 Thus, pregnant women require additional iodine intake. Probable causes of SCH are many and chronic autoimmune thyroiditis (e.g., Hashimoto’s disease, thyroiditis) with a prevalence of 3-8% in the general population is said to be the most common cause.20 The prevalence is said to be higher in women and increases with age.20 Drugs like lithium, amiodarone, interferon-a, interleukin-2, rifampicin, sunitinib and thalidomide,21 presence of goitrogens in diet is also reported from India as probable causes;22 micronutrient deficiency such as selenium and iron deficiency may cause hypothyroidism and goiter.23 Environmental toxins such as pesticides, fluoride, heavy metals may lead to hypothyroid state. High estrogen states (in pregnancy, it causes decrease in FT4 level),24 and chronic stress - both physical as well as mental25 along with other diseases like diabetes (specially type-1) are conditions affecting the pituitary or hypothalamus are some other causes.26 Women with family history of hypothyroidism or an autoimmune disease are also at increase risk of developing SCH. Radiation therapy used to treat cancers of the head and neck can cause

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problems with the thyroid gland.27 Thyroid surgery is more likely to develop a thyroid problem. de-Quervain’s thyroiditis is thought to be due to viral infection where there is transient hyperthyroidism followed by persistent hypothyroidism.28 Recommendations for screening: Baloch et al in 2003 found that more than 95% of rigorously screened normal euthyroid volunteers have serum TSH values between 0.4 and 2.5 mIU/L.29 Still universal screening of SCH by serum TSH, is not recommended in women with pregnancy without any evidence of fetal and maternal improvement with treatment of SCH. Serum TSH is the more accurate indication of thyroid status in pregnancy than any of the alternative (FT4, thyroid antibodies) methods, as declared by USPSTF 201130 and the gestation age for screening is 12-16 weeks of gestation. Routine screening of pregnant women after consultation by a physician has however been recommends by the American Association of Clinical Endocrinology (AACE). But, AACE recommends thyroid antibody test as the best screening test.31 It is noteworthy that controversy still remains over what is the best screening test in this situation (TSH or antibody). Indications for screening of high-risk group includes history of thyroid dysfunction or prior thyroid surgery, age >30 years, symptoms of thyroid dysfunction or the presence of goiter, thyroid peroxidase antibody (TPOAb) positivity, type 1 diabetes or other autoimmune disorders, history of miscarriage or preterm delivery (RPL), history of head or neck radiation, family history of thyroid dysfunction, morbid obesity (body mass index [BMI] ≥40 kg/m2), use of amiodarone or lithium, or recent administration of iodinated radiologic contrast, history of infertility and residing in an area of known moderate-to-severe iodine sufficiency. In view of the wide variation in the results of FT4 assays, method-specific and trimester-specific reference ranges of serum FT4 are required.30 It is very difficult to distinguish the symptoms of SCH from that of normal pregnancy as these are not always classical. There may be no signs and symptoms or mild general signs and symptoms of hypothyroidism, like depression, weight gain,32 dry or flaky skin, body weakness or feeling cold easily, slow pulse, low body temperature and increased need for sleep. Some women may experience difficulty in concentrating, irritability and anxiety with slow movement, thinking, and learning33 as well as slow circulation and heart rate.

OBSTETRICS AND GYNECOLOGY Diagnosis can be best done by serum TSH and FT4.34 tri-iodothyronine (FT3), total T3 and T4 are to be done when there is disturbed TSH level to know the secondary reason for hypothyroidism. Next step is antithyroid antibodies31 (maternal thyroid peroxidase) should be done in all cases where serum TSH is out of range. Other least important tests includes red cell selenium, urinary T3 (recent studies show that symptoms of hypothyroidism correlate best with 24-hour urinary FT3)35 urinary iodine concentration, thyroid ultrasound, serum cholesterol, which may be elevated in hypothyroidism, prolactin as a widely available test of pituitary function, testing for anemia and basal body temperature. These tests are important because the risk complications arising from hypothyroidism either overt or subclinical is very high. These includes a three-fold increase in risk of placental abruption and a two-fold risk of preterm delivery; reported in mothers with SCH.3 StagnaroGreen et al (2005)4 reported the higher prevalence of SCH in women with preterm delivery (before 32 weeks) compared to matched controls delivering at term. Neuromuscular symptoms and dysfunction are common in patients with SCH and can be reversed by levothyroxine treatment.36 Wilson et al37 found that the overall incidences of hypertension in pregnancy were 6.2%, 8.5% and 10.9% in the subclinical hyperthyroid, euthyroid and subclinical hypothyroid groups, respectively and were found to be significant when unadjusted (p = 0.016). After adjusting for confounding factors, there was a significant association between SCH and severe pre-eclampsia (adjusted odds ratio [OR] 1.6, 95% confidence interval [CI] 1.1-2.4; p = 0.03). Therefore, they recommend screening in every case of severe pre-eclampsia. The risk of developing gestational diabetes increases with thyrotropin level as reported by Tudela et al.38 This supports a relationship between SCH and diabetes diagnosed during pregnancy. It may progress to overt hypothyroidism in approximately 2-5% of cases annually.20 Pre-eclampsia, eclampsia and pregnancy-induced hypertension have a significantly higher incidence in SCH (15%; n = 7 of 45) compared with the incidence in the general population (7.6%).39 Neuromuscular symptoms and dysfunction.37 Postpartum thyroid dysfunction- significantly developed in presence of antithyroid antibody with a prevalence ranging from 1.1% to 16.7% with a mean of 7.5%.40 Postpartum depression can also occur but no significant difference was found.41 van der Zanden et al showed that SCH was found in 19.6% of women having history of vascular complicated pregnancy. It occurred

more often when pregnancy ended before 32 weeks of gestation (p = 0.008).42 Coming to the risk to fetus; 7-point reduction in intelligence quotient in children aged 7-9 years, whose mothers had SCH at pregnancy compared with the children of euthyroid mothers shown in a study by Haddow et al.1 However, in one study,1 even when hypothyroid pregnant women were insufficiently treated with levothyroxine (LT4), the intelligence quotient (IQ) scores of their offspring were not different from those of controls. Pregnant women with SCH have higher incidence of neonatal morbidity and mortality,43 although contradictory results have also been reported.10 Two-fold risk increase in neonate intensive care nursery admission (RR 1.8; 95% CI 1.12.9%) and incidence of respiratory distress syndrome defined as ventilator assistance >24 hours.3 Thyroid hormones are regulators of the mitochondrial activity so hypothesis can be made that all the complications in SCH may be due to mitochondrial dysfunction. It can be prevented providing a minimum of 250 Âľg iodine daily to all pregnant and lactating women (Level A-USPSTF). Preconception ingestion of 150 mg iodine daily along with preconception screening for hypothyroidism can prevent the major complications.30 The goal of treatment is to normalize maternal serum TSH values within the trimester-specific pregnancy reference range. If trimester-specific reference ranges for TSH are not available in the laboratory, the following reference ranges are recommended by USPSTF;31 first trimester (0.1-2.5 mIU/L) second trimester (0.2-3.0 mIU/L) third trimester (0.3-3.0 mIU/L). Recent guidelines proposed by the Antithyroid Association (ATA) and National Association of Clinical Biochemistry have stated that it is likely that in the future the upper limit of the serum TSH euthyroid reference range will be reduced to 2.5 mIU/L for all adults, because more than 95% of rigorously screened normal euthyroid volunteers have serum TSH values between 0.4 and 2.5 mIU/L.29 However, the American Association of Clinical Endocrinologists (AACE) and the Endocrine Society44 consensus panel have continued to recommend that 4.5 mIU/L be maintained as the upper limit of normal, reasoning that although some individuals within the range of 2.6-4.5 mIU/L may have subclinical thyroid disease, there is a lack of evidence of adverse outcome in this group. SCH has been associated with adverse maternal and fetal outcomes. However, due to the lack of randomized controlled trials, there is insufficient evidence to recommend for or against universal LT4 treatment in thyroglobulin antibody-negative (TAb-) pregnant

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OBSTETRICS AND GYNECOLOGY women with SCH (Level I-USPSTF). Women who are positive for (TPO-Ab) and have SCH should be treated with LT4. (Level B-USPSTF) 2010 Cochrane review of such potential interventions46 concluded that it may be useful to treat women with SCH that are also antithyroid antibody positive with exogenous thyroid hormone in an attempt to improve pregnancy outcomes. Surks et al45 found that the consequences of subclinical thyroid disease are minimal so they recommend against routine treatment of patients with TSH levels in these ranges. In light of the safety in pregnancy of levothyroxine (pregnancy category A drug), the AACE recommends treatment of all pregnant women, even those with SCH or positive TPO-Ab.46

gravity of the complications like abortion, preterm birth, weight gain, postpartum thyroiditis and converting to overt hypothyroidism in future, outweighs the cost of screening. The child may suffer from low IQ, decreased memory and concentrating power. In this view, we propose screening of all pregnant women in the first trimester by doing serum TSH and FT4 followed by antithyroid antibody for diagnosis. It should be made mandatory, so that not a single mother will be deprived of it. Finally, we conclude that treatment should be given to the antibody positive cases because complications are usually associated with it.

Abalovich et al43 studied a group of 114 women (16-39 years old) with primary hypothyroidism; of which 51 pregnancies (34%) were conceived under hypothyroidism (16 overt and 35 SCH) and 99 pregnancies were conceived under euthyroidism, while undergoing thyroid therapy. When treatment with levothyroxine was inadequate, the outcome of pregnancy was abortion (60% vs 71.4%), premature delivery (20% vs 7.2%) and term delivery (20% vs 21.4%) in overtly hypothyroid patients and subclinically hypothyroid patients, respectively. When treatment was adequate, term delivery (100% vs 90.5%) in overtly hypothyroid and subclinically hypothyroid patients respectively; there were no abortions in any of the groups. Abortions, premature and term deliveries in patients who were euthyroid on levothyroxine at the time of conception were 4%, 11.1% and 84.9%, respectively. So, they concluded that the evolution of pregnancies did not depend on whether the hypothyroidism was overt or subclinical but mainly on the treatment received. The adequate treatment of hypothyroidism during gestation minimizes risks and generally, makes it possible for pregnancies to be carried to term without complications.

1. Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999;341(8): 549-55.

Oral levothyroxine is the drug of choice as it is category A drug and has a long half-life (7 days) and is partially converted to T3 in the body, resulting in a constant physiological level of both T3 and T4 with a single daily dose. It should be started at a low-dose of 12.5-25 mg and the maintenance dose should be 2-2.4 mg/kg/day. Treatment significantly results in higher delivery rate as shown by Velkeniers et al.47 CONCLUSION The prevalence of SCH in South Asia especially in India is more than in other parts of the world and mostly due to autoimmune thyroiditis and nutrition deficiency. The

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References

2. Pop VJ, Kuijpens JL, van Baar AL, Verkerk G, van Son MM, de Vijlder JJ, et al. Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol (Oxf) 1999;50(2):149-55. 3. Casey BM, Dashe JS, Wells CE, McIntire DD, Byrd W, Leveno KJ, et al. Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 2005;105(2):239-45. 4. Stagnaro-Green A, Chen X, Bogden JD, Davies TF, Scholl TO. The thyroid and pregnancy: a novel risk factor for very preterm delivery. Thyroid 2005;15(4):351-7. 5. Gharib H, Tuttle RM, Baskin HJ, Fish LH, Singer PA, McDermott MT; American Association of Clinical Endocrinologists; American Thyroid Association; Endocrine Society. Consensus Statement #1: Subclinical thyroid dysfunction: a joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and The Endocrine Society. Thyroid 2005;15(1):24-8; response 32-3. 6. Klein RZ, Haddow JE, Faix JD, Brown RS, Hermos RJ, Pulkkinen A, et al. Prevalence of thyroid deficiency in pregnant women. Clin Endocrinol (Oxf) 1991;35(1): 41-6. 7. Nambiar V, Jagtap VS, Sarathi V, Lila AR, Kamalanathan S, Bandgar TR, et al. Prevalence and impact of thyroid disorders on maternal outcome in Asian-Indian pregnant women. J Thyroid Res 2011;2011:429097. 8. Sahu MT, Das V, Mittal S, Agarwal A, Sahu M. Overt and subclinical thyroid dysfunction among Indian pregnant women and its effect on maternal and fetal outcome. Arch Gynecol Obstet 2010;281(2):215-20. 9. Stagnaro-Green A. Thyroid antibodies and miscarriage: Where are we at a generation later? J Thyroid Res 2011;2011:841949.

OBSTETRICS AND GYNECOLOGY 10. Männistö T, Vääräsmäki M, Pouta A, Hartikainen AL, Ruokonen A, Surcel HM, ET et al. Perinatal outcome of children born to mothers with thyroid dysfunction or antibodies: a prospective population-based cohort study. J Clin Endocrinol Metab 2009;94(3):772-9. 11. Wang W, Teng W, Shan Z, Wang S, Li J, Zhu L, et al. The prevalence of thyroid disorders during early pregnancy in China: the benefits of universal screening in the first trimester of pregnancy. Eur J Endocrinol 2011;164(2):263-8. 12. Dhanwal DK, Prasad S, Agarwal AK, Dixit V, Banerjee AK. High prevalence of subclinical hypothyroidism during first trimester of pregnancy in North India. Indian J Endocrinol Metab 2013;17(2):281-4. 13. Ballabio M, Poshychinda M, Ekins RP. Pregnancy-induced changes in thyroid function: role of human chorionic gonadotropin as putative regulator of maternal thyroid. J Clin Endocrinol Metab 1991;73(4):824-31. 14. Glinoer D, de Nayer P, Bourdoux P, Lemone M, Robyn C, van Steirteghem A, et al. Regulation of maternal thyroid during pregnancy. J Clin Endocrinol Metab 1990;71(2): 276-87.

administration on hormonal and hepatic parameters in women with premature ovarian failure. J Clin Endocrinol Metab 1991;73(2):275-80. 25. Sapolsky RM, Krey LC, McEwen BS. The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. Endocr Rev 1986;7(3):284-301. 26. Ongphiphadhanakul B, Fang SL, Tang KT, Patwardhan NA, Braverman LE. Tumor necrosis factor-alpha decreases thyrotropin-induced 5’-deiodinase activity in FRTL-5 thyroid cells. Eur J Endocrinol 1994;130(5):502-7. 27. Rivkees SA. Pediatric Graves’ disease: controversies in management. Horm Res Paediatr 2010;74(5):305-11. 28. Sharma M, Aronow WS, Patel L, Gandhi K, Desai H. Hyperthyroidism. Med Sci Monit 2011;17(4):RA85-91. 29. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, FeldtRasmussen U, Henry JF, et al; Guidelines Committee, National Academy of Clinical Biochemistry. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 2003;13(1):3-126.

16. Glinoer D. The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocr Rev 1997;18(3):404-33.

30. Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R, et al; American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011;21(10):1081-125.

17. Dashe JS, Casey BM, Wells CE, McIntire DD, Byrd EW, Leveno KJ, et al. Thyroid-stimulating hormone in singleton and twin pregnancy: importance of gestational age-specific reference ranges. Obstet Gynecol 2005;106(4):753-7.

31. Gharib H, Cobin RH, Dickey RA. Subclinical hypothyroidism during pregnancy: position statement from the American Association of Clinical Endocrinologists. Endocr Pract 1999;5(6):367-8.

18. Casey BM, Dashe JS, Spong CY, McIntire DD, Leveno KJ, Cunningham GF. Perinatal significance of isolated maternal hypothyroxinemia identified in the first half of pregnancy. Obstet Gynecol 2007;109(5):1129-35.

32. Yeum CH, Kim SW, Kim NH, Choi KC, Lee J. Increased expression of aquaporin water channels in hypothyroid rat kidney. Pharmacol Res 2002;46(1):85-8.

15. van Raaij JM, Vermaat-Miedema SH, Schonk CM, Peek ME, Hautvast JG. Energy requirements of pregnancy in The Netherlands. Lancet 1987;2(8565):953-5.

19. Smyth PP, Hetherton AM, Smith DF, Radcliff M, O’Herlihy C. Maternal iodine status and thyroid volume during pregnancy: correlation with neonatal iodine intake. J Clin Endocrinol Metab 1997;82(9):2840-3. 20. Fatourechi V. Subclinical hypothyroidism: an update for primary care physicians. Mayo Clin Proc 2009;84(1):65-71. 21. Chakera AJ, Pearce SH, Vaidya B. Treatment for primary hypothyroidism: current approaches and future possibilities. Drug Design Devel Ther 2012;6:1-11. 22. Marwaha RK, Tandon N, Gupta N, Karak AK, Verma K, Kochupillai N. Residual goitre in the postiodization phase: iodine status, thiocyanate exposure and autoimmunity. Clin Endocrinol (Oxf) 2003;59(6):672-81. 23. Das S, Bhansali A, Dutta P, Aggarwal A, Bansal MP, Garg D, et al. Persistence of goitre in the post-iodization phase: micronutrient deficiency or thyroid autoimmunity? Indian J Med Res 2011;133:103-9. 24. Steingold KA, Matt DW, DeZiegler D, Sealey JE, Fratkin M, Reznikov S. Comparison of transdermal to oral estradiol

33. Samuels MH. Cognitive function in untreated hypothyroidism and hyperthyroidism. Curr Opin Endocrinol Diabetes Obes 2008;15(5):429-33. 34. Allahabadia A, Razvi S, Abraham P, Franklyn J. Diagnosis and treatment of primary hypothyroidism. BMJ 2009;338:b725. 35. Baisier WV, Hertoghe J, Eeckhaut W. Thyroid insufficiency. Is TSH measurement the only diagnostic tool? J Nutr Environmen Med 2000;10(2):105-13. 36. Christ-Crain M, Meier C, Huber PR, Staub JJ, Muller B. Effect of l-thyroxine replacement therapy on surrogate markers of skeletal and cardiac function in subclinical hypothyroidism. Endocrinologist 2004;14(3):161-6. 37. Wilson KL, Casey BM, McIntire DD, Halvorson LM, Cunningham FG. Subclinical thyroid disease and the incidence of hypertension in pregnancy. Obstet Gynecol 2012;119(2 Pt 1):315-20. 38. Tudela CM, Casey BM, McIntire DD, Cunningham FG. Relationship of subclinical thyroid disease to the incidence of gestational diabetes. Obstet Gynecol 2012;119(5):983-8.

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OBSTETRICS AND GYNECOLOGY 39. Wier FA, Farley CL. Clinical controversies in screening women for thyroid disorders during pregnancy. J Midwifery Womens Health 2006;51(3):152-8. 40. Stagnaro-Green A. Postpartum thyroiditis. Best Pract Res Clin Endocrinol Metab 2004;18(2):303-16. 41. Pop VJ, de Vries E, van Baar AL, Waelkens JJ, de Rooy HA, Horsten M, et al. Maternal thyroid peroxidase antibodies during pregnancy: a marker of impaired child development? J Clin Endocrinol Metab 1995;80(12):3561-6. 42. van der Zanden M, Hop-de Groot RJ, Sweep FC, Ross HA, den Heijer M, Spaanderman ME. Subclinical hypothyroidism after vascular complicated pregnancy. Hypertens Pregnancy 2013;32(1):1-10. 43. Abalovich M, Gutierrez S, Alcaraz G, Maccallini G, Garcia A, Levalle O. Overt and subclinical hypothyroidism complicating pregnancy. Thyroid 2002;12(1):63-8. 44. Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, et al. Subclinical thyroid disease: scientific review

and guidelines for diagnosis and management. JAMA 2004;291(2):228-38. 45. Reid SM, Middleton P, Cossich MC, Crowther CA. Interventions for clinical and subclinical hypothyroidism in pregnancy. Cochrane Database Syst Rev 2010;(7):CD007752. 46. Baskin HJ, Cobin RH, Duick DS, Gharib H, Guttler RB, Kaplan MM, Segal RL; American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract 2002;8(6):457-69. 47. Velkeniers B, Van Meerhaeghe A, Poppe K, Unuane D, Tournaye H, Haentjens P. Levothyroxine treatment and pregnancy outcome in women with subclinical hypothyroidism undergoing assisted reproduction technologies: systematic review and meta-analysis of RCTs. Hum Reprod Update 2013;19(3):251-8.

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Midlife Female Health Recommendations Released The North American Menopause Society (NAMS) has published a compilation of key points and clinical care recommendations to address the myriad issues facing women in midlife. Published in the October issue of Menopause, the NAMS Recommendations for Clinical Care of Midlife Women Working Group compiled the recommendations in celebration of the 25th anniversary of NAMS. They will be available free of charge on the NAMS Web site. “We are very excited about the 25th birthday of NAMS and thought what better way to advance our mission than to summarize recommendations for women’s care at midlife in a succinct, evidence-based publication that is freely available to all,” Jan L. Shifren, MD, lead author of the recommendations and president of NAMS told Medscape Medical News. “We hope these recommendations will educate clinicians and result in improved care for women at this complex life stage.” Dr Shifren is also a practicing gynecologist at Massachusetts General Hospital in Boston.

Stopping SSRIs before Pregnancy does not Reduce Miscarriages Women who take selective serotonin reuptake inhibitors (SSRIs) for depression during early pregnancy and those who stop taking the drugs up to a year before becoming pregnant have similar risks for miscarriage, investigators in a large, population-based study have found. The results suggest there is no causal relationship between SSRIs and miscarriage and that factors associated with mood disorders, such as smoking, alcohol use and poor compliance with prenatal care, may explain the increased risk among women who take antidepressants, write Jon Traerup Andersen, MD, PhD, and colleagues from the University of Copenhagen, Denmark.

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OBSTETRICS AND GYNECOLOGY

Incidence of First Trimester Miscarriage among Women Undergoing ICSI According to Origin of Sperm for Male Factor and Non-male Factor Alka Gahlot*, ML Swarankar†, Ravikant Soni‡

Abstract Prior to the development of intracytoplasmic sperm injection (ICSI), azoospermic and severely oligospermic men had little to no chance of having a biological child. In this study, ICSI outcome in 212 transfers with ejaculated spermatozoa and 44 transfers with surgically retrieved spermatozoa were evaluated. Material and methods: The 68 singleton gestations achieved by ICSI were segregated according to underlying infertility etiology, with 54.41% having male factor and 45.59% having female factor. None of the patients had coexisting infertility factor. Results: The miscarriage rate of all ICSI singleton gestations during the first trimester was 19.12%. There were no significant differences in early pregnancy loss (EPL) rate by infertility factor. Among patients undergoing ICSI because of male factor, there were no significant differences in EPL using ejaculated or nonejaculated sperm. Regardless of etiology, women aged ≥35 years had significantly higher EPL (36.36%). Conclusion: Our preliminary results demonstrate that first trimester miscarriage rates of ICSI gestations are not affected by underlying infertility etiology but are affected by maternal age.

Keywords: Intracytoplasmic sperm injection, infertility, miscarriage, pregnancy

ntracytoplasmic sperm injection (ICSI) has gained an increasing popularity due to its consistent fertilization rate and high pregnancy outcome. ICSI has been used largely to treat male factor infertility, with fertilization and pregnancy rates being comparable to those obtained in couples with good semen parameters undergoing standard in vitro insemination. The evident ability of ICSI to achieve high fertilization and pregnancy rates regardless of ejaculated semen parameters has extended its application to azoospermic patients. Injected epididymal and testicular spermatozoa have been used to effect fertilization and pregnancies. Original concerns about ICSI relating to its aggressiveness and arbitrary sperm selection have been eased by reports on the outcome and follow-up of the ICSI newborns. The presence of a significant frequency

*Associate Professor †Professor Dept. of Obstetrics and Gynecology ‡Senior Demonstrator Dept. of Biochemistry Mahatma Gandhi University of Medical Sciences and Technology, Jaipur, Rajasthan Address for correspondence Dr Alka Gahlot 170, Heera Nagar, DCM, Ajmer Road, Jaipur, Rajasthan - 302 021 E-mail: dralkagahlot@gmail.com, alkagahlot23@gmail.com

of Y chromosome microdeletions and karyotypic anomalies in men with nonobstructive azoospermia has raised concerns about the risks of treatment for these men. The etiology of azoospermia can be divided into obstructive and nonobstructive categories. The former is characterized by normal sperm production and is often caused by congenital mal-development of the vas deferens, a condition known to be associated with cystic fibrosis gene mutations. The treatment for obstructive azoospermia is microsurgical epididymal sperm aspiration (MESA), and when epididymal access is lacking testicular sampling is appropriate. Nonobstructive azoospermia is characterized by a varying degree of spermatogenic failure and at times is associated with an increased number of chromosomal abnormalities. The only method to retrieve spermatozoa from this form of azoospermia is by direct extraction of spermatozoa or germ cells from the testis. Women who are candidates for assisted reproduction technology have characteristics that may predispose them to an increased risk of miscarriage.1 Several studies have assessed miscarriage rates in in vitro fertilization (IVF) and ICSI pregnancies as well as the origin of spermatozoa utilized for assisted fertilization is considered in this regard.2 At present, almost half of fresh embryo transfers result from ICSI3 and

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OBSTETRICS AND GYNECOLOGY ICSI has become a routine laboratory service. Since, chromosomal abnormalities (mostly aneuploidy) have been reported to account for 50-75% of miscarriages during the first trimester of gestation,4 one measurable outcome to evaluate the safety of ICSI can be the rate of miscarriage among ICSI pregnancies. Conceivably, an increased rate of pregnancy loss may indicate an abnormal outcome related to ICSI as a technique. It is therefore important to document the survival rate of implanted gestations following ICSI and to compare these rates relative to underlying etiology of infertility. In this study, we report the first trimester survival rates of singleton gestations achieved by ICSI from patients with different types of infertility. Material and methodS The study was conducted prospectively from January 2012 to December 2012 at Jaipur Fertility Center, ART Division of Mahatma Gandhi University of Medical Sciences and Technology, Jaipur. Among the 256 patients who underwent ICSI, 68 (26.56%) were diagnosed as singleton gestations following embryo transfer. We excluded from this study all patients who had multiple gestation, monochorionic or heterotopic pregnancies or Frozen-Thawed embryo transfer. Couples having coexisting infertility factors or women with a history of recurrent pregnancy loss were also excluded from the study, as were couples known to have structural or numerical chromosomal aberrations. The remaining gestations were categorized according to the underlying etiology of infertility. Male factor cases were diagnosed according to the standards of the World Health Organization; tubal factor cases were diagnosed by either hysterosalpingogram or laparoscopy; polycystic ovarian syndrome (PCOS) was diagnosed by irregular menses, reversed folliclestimulating hormone (FSH): Luteinizing hormone (LH) ratio and sonographic appearance of ovaries; and all endometriosis cases were ≥II according to the American Fertility Society classification. Pregnancy was diagnosed as the presence of an intrauterine implanted embryo, defined as a gestational sac as determined by transvaginal ultrasonogram following ICSI and embryo transfer. A gestational sac was defined by the presence of an intrauterine hypoechoic area of ≥8 mm and covered by a double echogenic rim with a visible yolk sac (diameter ≥2 mm), as identified by a 6 MHz vaginal probe (Toshiba color Doppler N-10-30). A miscarriage was defined as the cessation or lack of detection of cardiac activity in the gestational sac or the inability to detect a previously defined gestational sac after vaginal bleeding during the 12 weeks following embryo transfer. Gestations with trophoblast regression

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but without sonographic evidence of pregnancy were not considered as miscarriages. All patients underwent scanning by transvaginal ultrasonogram 4 weeks (28-30 days) after embryo transfer. None of the gestations evaluated started as a multiple type followed by subsequent vanishing of embryos. All patients continued to receive progesterone, 100 mg IM once or 200 mg vaginally 8-hourly daily as luteal phase support for 12 weeks after embryo transfer. All couples were thoroughly informed about the treatment procedures, and written informed consent was obtained from all patients. Statistical analyses were performed using the χ2 test, p < 0.05 was considered statistically significant. Results When we diagnosed infertility factors among the recruited couples with positive pregnancy, we found that 37 (54.41%) were due to male factor and 31 (45.59%) were due to female factors including tubal factor, endometriosis, PCOS, other factors such as hyperprolactinemia, hypogonadotropic, hypogonadism, myoma uteri, uterine dysconfiguration, genital tuberculosis or secondary infertility. The mean age of the women was 32.14 years, and the mean age of their spouses was 35.02 years. The miscarriage rates in singleton gestations did not significantly differ according to underlying infertility factor, 21.62% versus 16.13% in male and female infertility, respectively (p > 0.05). During the first trimester overall 13 (19.12%) patients experienced pregnancy loss (Table 1). Miscarriage rate was significantly higher in women aged ≥35 years than in younger women (36.36% versus 10.86%, p < 0.05). However, when the infertility categories were divided according to age (<35 vs ≥35 years), older patient with male factor, had increased rates of miscarriage compared with younger patients, which is not statistically significant (Table 2). Among patients with male factor infertility, there was no significant difference in miscarriage rates when surgically retrieved sperm 25% or ejaculated sperm 20% were used for ICSI. Miscarriage rates also did not differ significantly in patients undergoing assisted reproduction treatment with ICSI because of female factor 16.13% (p > 0.05) (Table 3). Table 1. Miscarriage Rates of Gestations by Infertility Factor No. of pregnancies (%)

No. of miscarriage (%)

Male factor

37/68 = 54.41

8/37 = 21.62

Female factor

31/68 = 45.59

5/31 = 16.13

13/68 = 19.12

Total

OBSTETRICS AND GYNECOLOGY Table 2. Outcome of Gestations by Infertility Factor and Maternal Age <35 years No. of pregnancy (%)

â&#x2030;Ľ35 years

No. of miscarriage (%)

P value

No. of pregnancy (%)

No. of miscarriage (%)

Male factor

25/46 = 54.35

3/25 = 12

12/22 = 54.55

5/12 = 41.67

0.104 NS

Female factor

21/46 = 45.65

2/21 = 9.5

10/22 = 45.45

3/10 = 30

0.354 NS

5/46 = 10.86

8/22 = 36.36

0.030 S

Total

Table 3. Miscarriage Rates among Women Undergoing ICSI According to Origin of Sperm for Male Factor and Non-male Factor No. of pregnancy

No. of miscarriage (%)

Surgically retrieved spermatozoa

3/12 = 25

Ejaculated spermatozoa (male factor)

5/25 = 20

Ejaculated spermatozoa (non-male factor)

5/31 = 16.13

Total

13/68 = 19.12

Discussion Human reproduction is not efficient; with the majority of conceptions being lost very early in gestational life.5 Implanted embryos may undergo developmental arrest at any point during early gestational life. Pregnancies achieved by the use of assisted reproduction technologies; however, are easier to follow than those conceived spontaneously, offering the opportunity to observe early gestational life ultrasonographically. Miscarriage significantly reduces the initial success and efficacy of assisted reproduction treatment, as well as increasing the psychological burden on patients. Couples who are planning assisted reproduction pregnancies should be informed of the potential hazards of these methods, enabling them to be aware of any potential risk factors that may cause miscarriage. Several studies have reported miscarriage rates in ICSI pregnancies, and have compared rates in IVF and spontaneous pregnancies. Whereas most have found no significant differences in early miscarriage rates, one study found that the early pregnancy loss rate was significantly lower in ICSI (11%) than in IVF (24%) pregnancies.6 Although, there are no randomized data on miscarriage rates following ICSI and IVF,7 early pregnancy and perinatal outcomes of ICSI gestations appear not to be different from those of IVF gestations.8 In addition, no clinical effects of ICSI severe enough to cause a miscarriage during the first trimester have been reported.9 It has been suggested that offspring from ICSI carry an increased rate of chromosomal aberrations.10 Those abnormalities; however, seem to be related to the underlying parental risk of abnormality and not to the ICSI procedure itself. Although patients

undergoing assisted reproduction treatment have a higher rate of miscarriage than do fertile patients, these differences in loss rates are not completely understood and may originate from predisposing factors that are more prevalent in patients suffering from infertility.1 Some studies recently reported that prenatal karyotypes of fetuses in pregnancies achieved by ICSI for male factor infertility did not differ from fetal karyotypes in pregnancies achieved by ICSI for non-male factor infertility.11 Furthermore, IVF and ICSI pregnancies that aborted during the first trimester showed no significant differences in the incidence of embryonic anomalies.12 In the majority of reports, ICSI procedures have been performed in cases of male factor infertility, which may eventually pose a risk to the offspring. Therefore, we studied segregated gestations according to male and female factor infertility. Male factor infertility was further subdivided into groups in which ejaculated sperm and nonejaculated sperm were used. The impact of sperm origin and quality on miscarriage rates was assessed among ICSI pregnancies. No differences in miscarriage rates have been reported in patients undergoing ICSI for male factor or IVF for non-male factor, and semen origin was found not to affect the miscarriage rate in both sets of patients.13 In support to our findings, the miscarriage rate has been reported to be higher in gestations using surgically retrieved sperm than in those using ejaculated sperm,14 although others have reported similar results for both groups.15 Our results confirm that first trimester survival rates of singleton gestations did not differ when patients with non-male factor infertility underwent ICSI. In agreement with previous studies, we observed an

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OBSTETRICS AND GYNECOLOGY increased risk of miscarriage with increasing maternal age.16 The current study differs in two ways from similar studies evaluating miscarriage rates in ICSI pregnancies. The earlier studies used the demonstration of a fetal heartbeat to define pregnancy. This method; however, may miss a significant number of implanted embryos following transfer, which would have been detected by the presence of a gestational sac, even in the absence of cardiac motion. In other words, this method may underestimate the lifespan of earliest stage implanted embryos, which would have been detected by ultrasonographic visualization. A study recently demonstrated vanishing embryos in multiple gestations by using the presence of a gestational sac as a landmark17 indicating that this approach would better evaluate the intrauterine fate of implanted ICSI embryos. In contrast to most other studies evaluating miscarriage rates in ICSI pregnancies, we evaluated miscarriage rates only in singleton gestations. Most of the earlier studies assessing early pregnancy loss in ICSI pregnancies did not account for multiple fetuses and defined abortion as the total miscarriage of the pregnancy. During early gestational life, a significant number of multiple gestations can have spontaneous reductions, which should be considered in calculations of abortion rates.17 In addition, the survival rates of singleton gestations differ from those of multiple gestations during the first trimester.18 Data support the idea that performing ICSI in all cases of assisted reproduction is not advantageous, and probably it is only more expensive and time consuming.19 conclusion We have shown that first trimester miscarriage rates in singleton gestations achieved by ICSI were not affected by the underlying infertility factor, but were affected by maternal age. References 1. Ezra Y, Schenker JG. Abortion rate in assisted reproductiontrue increase? Early Pregnancy 1995;1(3):171-5. 2. Schieve LA, Tatham L, Peterson HB, Toner J, Jeng G. Spontaneous abortion among pregnancies conceived using assisted reproductive technology in the United States. Obstet Gynecol 2003;101(5 Pt 1):959-67. 3. H uman Fertilisation and Embryology Authority. For Patients; Information and Guide. URL: http:// wwwhfeagovuk. 2000. 4. Philipp T, Philipp K, Reiner A, Beer F, Kalousek DK. Embryoscopic and cytogenetic analysis of 233 missed abortions: factors involved in the pathogenesis of developmental defects of early failed pregnancies. Hum Reprod 2003;18(8):1724-32.

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5. Macklon NS, Geraedts JP, Fauser BC. Conception to ongoing pregnancy: the ‘black box’ of early pregnancy loss. Hum Reprod Update 2002;8(4):333-43. 6. Orvieto R, Ben-Rafael Z, Ashkenazi J, Yoeli R, Messing B, Perri T, et al. Outcome of pregnancies derived from assisted reproductive technologies: IVF versus ICSI. J Assist Reprod Genet 2000;17(7):385-7. 7. van Rumste MM, Evers JL, Farquhar CM. ICSI versus conventional techniques for oocyte insemination during IVF in patients with non-male factor subfertility: a Cochrane review. Hum Reprod 2004;19(2):223-7. 8. Kozinszky Z, Zádori J, Orvos H, Katona M, Pál A, Kovács L. Obstetric and neonatal risk of pregnancies after assisted reproductive technology: a matched control study. Acta Obstet Gynecol Scand 2003;82(9):850-6. 9. American Society for Reproductive Medicine; Society for Assisted Reproductive Technology Registry. Assisted reproductive technology in the United States: 1999 results generated from the American Society for Reproductive Medicine/Society for Assisted Reproductive Technology Registry. Fertil Steril 2002;78(5):918-31. 10. Bonduelle M, Van Assche E, Joris H, et al. Prenatal testing in ICSI pregnancies: incidence of chromosomal anomalies in 1586 karyotypes and relation to sperm parameters. Hum Reprod 2002;17(10):2600-14. 11. Jozwiak EA, Ulug U, Mesut A, Erden HF, Bahçeci M. Prenatal karyotypes of fetuses conceived by intracytoplasmic sperm injection. Fertil Steril 2004;82(3):628-33. 12. Causio F, Fischetto R, Sarcina E, Geusa S, Tartagni M. Chromosome analysis of spontaneous abortions after in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Eur J Obstet Gynecol Reprod Biol 2002;105(1):44-8. 13. Palermo GD, Neri QV, Hariprashad JJ, et al. ICSI and its outcome. Semin Reprod Med 2000;18(2):161-9. 14. Anderson AR, Wiemer KE, Weikert ML, Kyslinger ML. Fertilization, embryonic development and pregnancy losses with intracytoplasmic sperm injection for surgically-retrieved spermatozoa. Reprod Biomed Online 2002;5(2):142-7. 15. Göker EN, Sendag F, Levi R, Sendag H, Tavmergen E. Comparison of the ICSI outcome of ejaculated sperm with normal, abnormal parameters and testicular sperm. Eur J Obstet Gynecol Reprod Biol 2002;104(2):129-36. 16. Nybo Andersen AM, Wohlfahrt J, Christens P, Olsen J, Melbye M. Maternal age and fetal loss: population based register linkage study. BMJ 2000;320(7251):1708-12. 17. Ulug U, Jozwiak EA, Mesut A, et al. Survival rates during the first trimester of multiple gestations achieved by ICSI: a report of 1448 consecutive multiples. Hum Reprod. 2004;19(2):360-4. 18. Tummers P, De Sutter P, Dhont M. Risk of spontaneous abortion in singleton and twin pregnancies after IVF/ICSI. Hum Reprod 2003;18(8):1720-3. 19. Borini A, Gambardella A, Bonu MA, et al. Comparison of IVF and ICSI when only few oocytes are available for insemination. Reprod Biomed Online 2009;19(2):270-5.

OBSTETRICS AND GYNECOLOGY

Predictive Value of Endometrial Thickness, Pattern and E2 Level on Day of hCG Administration in IVF-ET Cycles Alka Gahlot*, ML Swarankar†, Ravikant Soni‡

Abstract Objective: To evaluate the effect of endometrial thickness, pattern and E2 level on the day of human chorionic gonadotropin (hCG) administration on clinical outcome in patients undergoing in vitro fertilization and embryo transfer (IVF-ET). Method: A total number of 112 cycles of IVF-ET conducted at Jaipur Fertility Centre, an Infertility Unit of Mahatma Gandhi University of Medical Sciences and Technology, Jaipur were observed prospectively. Endometrial ultrasonographic characteristics and E2 levels were recorded on the day of hCG administration. Clinical pregnancy rates were analyzed with different endometrial thickness and E2 levels. Results: Overall 37.5% patients conceived and in these women endometrial thickness was between 6-14 mm. Only 2.38% patients conceived with an ET of <6 mm. Maximum patients (52.33%) who conceived were with an ET of 8-10 mm. It was observed that endometrial thickness pattern did not have significant effect on clinical pregnancy rate in these cases. Clinical pregnancy rate was significantly higher in patients with serum E2 levels between 1,000-2,500 pg/mL as compared to other two groups. Conclusion: When thin endometrium ≤6 mm with no triple-line coexist and serum E2 level is >2,500 pg/mL in IVF/ICSI-ET, candidate cryopreservation should be recommended.

Keywords: In vitro fertilization, clinical pregnancy rate, embryo transfer

t is generally accepted that endometrial receptivity is critical to successful pregnancy. Ultrasonographic examination is routinely performed in ART treatment because of accurate evaluation and noninvasive detection. Indeed, both endometrial thickness and endometrial pattern have been regarded as prognostic parameters for successful pregnancy in in vitro fertilization and embryo transfer (IVF-ET).

Following the periodic stimulation of ovarian hormone, the changes in endometrial structure during the menstrual cycle can be identified easily by ultrasound examination.1 In an IVF-ET procedure, human chorionic gonadotropin (hCG) is used as a substitute for the natural luteinizing hormone (LH) -surge to trigger the final maturity of oocyte. Evaluation of

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endometrium on the day of hCG administration is of great clinical importance.2,3 Several studies have demonstrated the existence of a correlation between endometrial characteristics and pregnancy rate in IVF-ET patients.4-6 However, the correlation proposed in these studies has not been universally accepted.7 There also is no consensus on whether the endometrial ultrasound characteristics can predict the pregnancy outcome in IVF treatment. Weissman et al reported an increase in miscarriage rate when an endometrial thickness of >14 mm was found on day of hCG injection.8 However, data from more recent studies do not support this finding.9 A no triple-line pattern seems to be a prognostic sign of less favorable outcome, while a triple line pattern appears to be associated with conception.10 Despite the abundance of studies that have evaluated the effect of endometrial characteristics on clinical outcome in IVF-ET patients studies on the combined predictive role of endometrial thickness and pattern are lacking. In this study, we examined the correlation between endometrial thickness, pattern and serum E2 level on day of hCG administrations and IVF outcome. Serum E2 levels <1,000 and >2,500 pg/mL were associated with less favorable outcome in IVF/ICSI/ET

OBSTETRICS AND GYNECOLOGY cycles in comparison to serum E2 level between 1,000-2,500 pg/mL.

after ET. Early miscarriage was defined as pregnancy ending before 12 weeks of gestation.

Material and Methods

In short protocol, each patient received daily injection of GnRh-agonist along with r-FSH and HMG.

Cycles of IVF/ICSI/ET were conducted at Jaipur Fertility Centre and Infertility Unit of Mahatma Gandhi University of Medical Sciences and Technology, Jaipur. Since, vaginal sonography and serum E2 level assessment on the day of hCG administration was done routinely in the center, the consent of women who participated in the study was not necessary. All fresh IVF or ICSI treatment cycles that used long protocol (mid-luteal phase gonadotropin-releasing hormone (GnRh)-agonist suppression), short protocol (GnRh-agonist from Day 3 of cycle) as method of ovarian stimulation and reached oocyte pick up and ET within the study period were included, regardless of diagnosis, reproductive history or insemination method. Cycles using donor oocyte or cryopreserved embryos were excluded from this study. Other exclusion criteria included: Age >40 years and the presence of known endometrial anomalies. IVF/ICSI/ET Treatment Protocol For ovarian stimulation, utilizing the long protocol procedure, each patient received single daily subcutaneous (SC) dose of GnRh-agonist till spontaneous menstruation occurred or total dose of 14 injections of GnRh-agonist if there was no spontaneous occurrence of menstruation. A vaginal ultrasound examination and serum follicle-stimulating hormone (FSH), LH and E2 measurements were performed. When the FSH level were <12 mIU/mL, LH levels were <5 mIU/mL and E2 levels were <80 pg/mL, and the largest follicle diameter was <10 mm without ovarian cyst, controlled ovarian hyperstimulation (COH) was performed. COH was achieved with administration of gonadotrophins including the recombinant FSH and/or human menopausal gonadotropin (HMG). The initial doses of gonadotrophins ranged from 150 to 450 IU, depending on the basal FSH level, maternal age, antral follicular count. Once 3 or more follicles reached a diameter >17 mm, hCG was administered. Oocyte were retrieved within 34-36 hours and ET was performed 3-5 days afterwards. All patients were given IM or vaginal progesterone daily starting on the day of oocyte retrieval. Serum b-hCG levels were measured 14-15 days after ET. Subsequent ultrasound examinations were performed at a gestational age of 6 weeks. Clinical pregnancy was defined as identification of a gestational sac 4 weeks

Ultrasound Examination After a true longitudinal view of the uterus has been obtained on the day of hCG administration, the endometrial thickness was measured as the maximum thickness between the highly reflective interfaces of the endometrial-myometrial junction. The measurement included both layers of endometrium. The surrounding low-amplitude echo layer was excluded, because it represents the inner layer of the myometrium. All cycles were divided into three groups depending on the thickness: Group I: <6 mm; Group II: 6-12 mm; Group III: >12 mm. Endometrial pattern is defined as type of relative echogenicity of the endometrium compared with adjacent myometrium.2 In our study, we classify all pattern into two types. Pattern A (tripleline) was described as hypoechoic endometrium with well-defined hyperechoic outer walls and a central echogenic line; pattern B (no triple-line) was defined as isoechoic or homogeneous hyperechoic endometrium with a nonprominent or absent central echogenic line. Serum E2 levels were estimated by VIDAS using ELFA technique on day of hCG administration. Results Total number of patients recruited were 112. Their mean FSH was 5.0 mIU/mL, mean endometrial thickness was 8.7 mm, mean age was 30.53 years, mean duration of infertility was 8.2 years. 76.79% patients had primary infertility and 23.21% had secondary infertility (Table 1). Overall, 37.5% patients conceived, and in these women, the endometrial thickness was between 6-14 mm. Duration of stimulation was variable till at least 4 follicles were >17 mm. Most of our subjects (86.32%) had a triple-line pattern on day of hCG administration. Pattern A was detected more frequently in Group II than in Group I and III (p > 0.05), not significant statistically (Table 2). There was no difference in clinical pregnancy rates (CPR) between patterns. To evaluate role of endometrial thickness in pregnancy outcome, clinical pregnancy rates were evaluated at a difference of every 2 mm of endometrial thickness. Pregnancy rates ranged from 2.38% among patients

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OBSTETRICS AND GYNECOLOGY with an endometrial thickness of ≤6 mm to 52.38% among patients with an endometrial thickness of 8-10 mm (p < 0.001). Only one pregnancy was achieved with an endometrial thickness of <6 mm and two when

the thickness was between 12-14 mm. Endometrial thickness threshold of 6 mm was observed below, which pregnancy rate decreased rapidly. Clinical pregnancy rate out of patients conceived was 2.38% with endometrial thickness ≤6 mm. Rest 97.62% were having endometrial thickness between 6-14 mm. The difference in clinical pregnancy rates between different endometrial thickness groups being statistically significant (p < 0.001). Overall, 37.50% patients conceived and in these women endometrial thickness was between 6-14 mm (Table 3).

Table 1. Baseline Cycle Characteristics Variable

Mean

Maternal age (years)

30.53

Baseline FSH (mIU/mL)

5.0

Endometrial thickness (mm)

8.7

E2 on hCG day (pg/mL)

1,663.6

P on hCG day (ng/mL)

1.01

When grouped according to serum E2 levels on day of hCG administration, it was observed that the clinical pregnancy rate was significantly higher in patients with serum E2 level between 1,000-2,500 pg/mL as compared to other two groups (p < 0.05), which is statistically significant (Table 4).

Etiology of infertility 25%

Tubal factor Ovulatory factor

8.03%

Endometriosis

1.79%

Uterine factor

4.46%

Male factor

35.71%

Unexplained

18.75%

Combined factor

6.25%

Discussion Both endometrial thickness and E2 levels are useful as prognostic parameters for successful pregnancy in IVF/ICSI and ET. Endometrial receptivity is crucial to implantation of embryo. There is lack of agreement with regard to the minimum endometrial thickness required

Table 2. Distribution of Endometrial Pattern in Three Endometrial Groups (the Percentage of Endometrial Pattern are Shown for Individual Endometrial Thickness Group) Endometrial thickness

Endometrial pattern Pattern A (triple-line) (n = 95)

Pattern B (no triple-line) (n = 17)

8/95 = 8.42%

2/17 = 11.77%

6-12 mm

82/95 = 86.32%

12/17 = 70.59%

>12 mm

5/95 = 5.26%

3/17 = 17.65%

<6 mm

Table 3. Clinical Outcome by Individual Endometrial Thickness No. of cycles (n = 112)

No. of pregnancy (n = 42)

Nonpregnant (n = 70)

Percentage (%)

≤6 mm

2.38

6-8 mm

9.52

8-10 mm

52.38

10-12 mm

12-14 mm

4.76

>14 mm

112

37.5

Endometrial thickness

Total

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OBSTETRICS AND GYNECOLOGY Table 4. Correlation Between E2 Level on Day of hCG Administration and Clinical Pregnancy E2 level on day of hCG administration

No. of patients

Clinical pregnancy

Percentage (%)

<1,000 pg/mL

9/42 = 21.43

1,000-2,500 pg/mL

23/42 = 54.76

>2,500 pg/mL

10/42 = 23.80

Total

112

42/112 = 37.50

for successful pregnancy. Several studies found that a minimal endometrial thickness 6 mm is acceptable for implantation.11,12 Sundstrom reported a successful pregnancy with an endometrial thickness as little as 4 mm.13 In our study, the thinnest endometrial lining for successful pregnancy was 4.8 mm and maximum no. of conception occurred when thickness was 8-10 mm. With increasing endometrial thickness (>14 mm) a high miscarriage rate was reported by Weissman,8 which was not observed in the present study as no woman conceived with endometrial thickness >14 mm. A relatively low pregnancy rate was observed in patients with endometrial thickness <6 mm suggesting that more attention needs to be given to ET to such patients. In our study, the overall clinical pregnancy rate was 37.50%. We found that endometrial echo patterns have no prognostic value for pregnancy.7 Several studies have suggested that a premature secretory endometrial pattern is introduced by the advanced progesterone rise, and this premature conversion has an adverse effect on pregnancy rates. In our study, increased progesterone concentration were not found in no triple-line pattern. The reason for no triple-line endometrial pattern observed prior to ovulation is not known and cannot be explained by higher progesterone levels. Coexistence of a thinner endometrium in association with no triple-line pattern reflects a diminished endometrial responsiveness to ovarian hormones and poor receptivity of endometrium, leading to a low clinical pregnancy rate and poor clinical outcome. When the patients were grouped according to serum E2 levels on the day of hCG administration, it was found that CPR was significantly higher in patients with serum E2 levels between 1,000-2,500 pg/mL as compared to the other two groups.

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Conclusion In conclusion, when thin endometrium â&#x2030;¤6 mm and no triple-line endometrial pattern coexist in IVF/ICSI-ET candidate, cryopreservation should be recommended. If thin endometrium with good texture (triple-line) is present, other prognostic factors, such as embryo quality should be taken into consideration. When serum E2 levels is >2,500 pg/mL then cryopreservation of embryo should be considered as along with decreased pregnancy rate it is also associated with increased chances of OHSS. References 1. Killick SR. Ultrasound and the receptivity of the endometrium. Reprod Biomed Online 2007;15(1):63-7. 2. Friedler S, Schenker JG, Herman A, Lewin A. The role of ultrasonography in the evaluation of endometrial receptivity following assisted reproductive treatments: a critical review. Hum Reprod Update 1996;2(4):323-35. 3. Oliveira JB, Baruffi RL, Mauri AL, Petersen CG, Borges MC, Franco JG Jr. Endometrial ultrasonography as a predictor of pregnancy in an in-vitro fertilization programme after ovarian stimulation and gonadotrophinreleasing hormone and gonadotrophins. Hum Reprod 1997;12(11):2515-8. 4. Noyes N, Liu HC, Sultan K, Schattman G, Rosenwaks Z. Endometrial thickness appears to be a significant factor in embryo implantation in in-vitro fertilization. Hum Reprod 1995;10(4):919-22. 5. Richter KS, Bugge KR, Bromer JG, Levy MJ. Relationship between endometrial thickness and embryo implantation, based on 1,294 cycles of in vitro fertilization with transfer of two blastocyst-stage embryos. Fertil Steril 2007;87(1):53-9. 6. Al-Ghamdi A, Coskun S, Al-Hassan S, Al-Rejjal R, Awartani K. The correlation between endometrial thickness and outcome of in vitro fertilization and embryo transfer (IVF-ET) outcome. Reprod Biol Endocrinol 2008;6:37.

OBSTETRICS AND GYNECOLOGY 7. Rashidi BH, Sadeghi M, Jafarabadi M, Tehrani Nejad ES. Relationships between pregnancy rates following in vitro fertilization or intracytoplasmic sperm injection and endometrial thickness and pattern. Eur J Obstet Gynecol Reprod Biol 2005;120(2):179-84. 8. Weissman A, Gotlieb L, Casper RF. The detrimental effect of increased endometrial thickness on implantation and pregnancy rates and outcome in an in vitro fertilization program. Fertil Steril 1999;71(1):147-9. 9. Dietterich C, Check JH, Choe JK, Nazari A, Lurie D. Increased endometrial thickness on the day of human chorionic gonadotropin injection does not adversely affect pregnancy or implantation rates following in vitro fertilization-embryo transfer. Fertil Steril 2002;77(4): 781-6. 10. Check JH, Lurie D, Dietterich C, Callan C, Baker A. Adverse effect of a homogeneous hyperechogenic endometrial sonographic pattern, despite adequate endometrial thickness on pregnancy rates following invitro fertilization. Hum Reprod 1993;8(8):1293-6.

11. Gonen Y, Casper RF. Prediction of implantation by the sonographic appearance of the endometrium during controlled ovarian stimulation for in vitro fertilization (IVF). J In Vitro Fert Embryo Transf 1990;7(3):146-52. 12. Gonen Y, Casper RF, Jacobson W, Blankier J. Endometrial thickness and growth during ovarian stimulation: a possible predictor of implantation in in vitro fertilization. Fertil Steril 1989;52(3):446-50. 13. Sundström P. Establishment of a successful pregnancy following in-vitro fertilization with an endometrial thickness of no more than 4 mm. Hum Reprod 1998;13(6):1550-2. 14. Kovacs P, Matyas S, Boda K, Kaali SG. The effect of endometrial thickness on IVF/ICSI outcome. Hum Reprod 2003;18(11):2337-41. 15. Zhang X, Chen CH, Confino E, Barnes R, Milad M, Kazer RR. Increased endometrial thickness is associated with improved treatment outcome for selected patients undergoing in vitro fertilization-embryo transfer. Fertil Steril 2005;83(2):336-40.

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New Guidelines for Calculating the Estimated Due Date The American College of Obstetricians and Gynecologists (ACOG), the American Institute of Ultrasound in Medicine (AIUM), and the Society for Maternal-Fetal Medicine (SMFM) have developed new guidelines for calculating the estimated due date (EDD) in order to help correct the current variability in the calculation of pregnancy due dates and gestational age and facilitate consistent care of pregnant women and their babies. The guidelines will be published in Obstetrics & Gynecology and the Journal of Ultrasound in Medicine.

Robotic Surgery More Costly for Ovarian Problems, Study Says We’ve heard it before - the robots are coming to save the day. But for certain medical procedures, that day may not be as close as you’d think. A study published today in the journal Obstetrics & Gynecology suggests that robot-assisted surgeries to remove ovaries or ovarian cysts were more expensive and had more complications than traditional minimally invasive surgeries. Removing ovaries and cysts with the help of a robot cost about $2,500 and $3,300 more, respectively, than laparoscopic or “keyhole” surgeries. That can add upward of 80 percent to the cost of a surgery. What’s more, women whose surgeries had been performed with the help of a robot were slightly more likely to have complications such as a bladder injury, bowel obstruction or excessive bleeding.

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OBSTETRICS AND GYNECOLOGY

Correlation Between D&C, USG and Hysteroscopy Findings in Diagnosing a Cause for Abnormal Uterine Bleeding Ridhi Kathuria*, Beena Bhatnagarâ&#x20AC;

Abstract Introduction: Abnormal uterine bleeding (AUB) is the most often encountered gynecological problem. A newly coined term describes the condition wherein there is any deviation from a normal menstrual pattern. An estimated 5% women aged 30-49 years consult a gynecologist each year for treatment. This makes it imperative to accurately diagnose and treat the cause. This study aims at judging the place of diagnostic hysteroscopy in obtaining an accurate diagnosis of the etiology of AUB and amp; outlining a mode of treatment. This is done by correlating the findings on hysteroscopy and those found on a dilation and curettage (D&C) and ultrasonography (USG). Material and methods: This prospective study was performed in the Dept. of Obstetrics and Gynecology, National Institute of Medical Sciences, Jaipur. Fifty cases of AUB were chosen based on inclusion and exclusion criteria. The patients were subjected to routine investigations, USG, D&C and hysteroscopy. The findings of the three were compared and analyzed. Results: AUB was most common between 30-39 years (44%). Maximum patients had complaints since 3-6 months (50%). Menorrhagia was the most common presenting complaint (46%). Normal findings were observed in 40% cases with D&C, 16% with USG, 22% with hysteroscopy. Abnormal findings were seen in 60% cases with D&C, 84% with USG, 78% with hysteroscopy. The over-diagnostic role of USG is also highlighted. Conclusion: This study reveals the superior ability of hysteroscopy in evaluating patients with AUB, when compared to D&C and USG. These findings are in agreement with those of many other studies.

Keywords: Abnormal uterine bleeding, diagnostic hysteroscopy, dilation and curettage, ultrasonography

bnormal uterine bleeding (AUB) term is newly coined for describing the condition wherein there is any deviation from a normal menstrual pattern. It includes both dysfunctional uterine bleeding (DUB) and bleeding from structural causes. Awwad et al described DUB as a common debilitating problem amongst women in all age groups and accounting for 20% of gynecology OPD visits1 and may account for 25% of all hysterectomies.2

DUB is the commonest cause of iron deficiency in the developed world and of chronic illness in the developing world too.3 An estimated 5% of women aged 30-49 years will consult her gynecologist each year for the treatment of menorrhagia.

*3rd Year Resident â&#x20AC; Professor and Head Dept. of Obstetrics and Gynecology National Institute of Medical Sciences, Jaipur, Rajasthan Address for correspondence Dr Ridhi Kathuria C/o: Vijay Nursing Home F-24/25, Sector-3, Rohini, New Delhi - 110 085 E-mail: ridhi.kathuria@yahoo.com

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About 30% of all women report having had menorrhagia.4 However, these definitions are open to objection, as modern day diagnostic tools like, endometrial biopsy, vaginal smears, hysteroscopy, diagnostic laparoscopy can largely outline a cause of such abnormal bleeding. Clinical management aims at obtaining an accurate diagnosis and charting out the correct line of treatment. Clinical history, physical and pelvic examination attempts to determine the site and source of the bleeding. Conventional interventions consist of ultrasonography (USG), followed by a diagnostic dilation and curettage (D&C). USG only shows the uterine contour and the status of the ovary, but fails to provide adequate information regarding the endometrium. D&C is a blind procedure and the endometrium has to be sent to the pathologist to study. It also requires skill so as to obtain an adequate sample of the endometrial tissue. Complications like perforations, cervical tears and injuries, scar tissue formation and intrauterine adhesions are common. Hysteroscopy in this new era is increasingly becoming a prime investigation of

OBSTETRICS AND GYNECOLOGY choice for the evaluation of AUB. Owing to the direct visualization of the uterine cavity, it is able to pinpoint the etiology in most of the cases.5 It can most accurately detect endometrial polyps, fibroids, hyperplasia, etc., better than an ultrasound scan wherein the diagnosis is often missed.6 This study is aimed at judging the place of diagnostic hysteroscopy in obtaining an accurate diagnosis of the etiology of AUB and outlining a mode of treatmentspecific to the cause. This is done by correlating the findings on hysteroscopy and those found on a D&C. MATERIAL AND METHODS A prospective design study, which was performed in the Dept. of Obstetrics and Gynecology, National Institute of Medical Sciences, Jaipur.

ÂÂ

Table 1. Age Incidence of AUB Age group

No. of patients 4

30-39

40-49

50-60

The materials included all the AUB patients attending the OPD and were admitted for hysteroscopy and D&C. Fifty cases of AUB were taken for the study. Any comorbid illness was excluded. All the patients in the study were subjected through detailed history taking, general physical examination, specific examination in the form of per speculum and per vaginal examination (unless actively bleeding). Routine blood and urine investigations (hemoglobin [Hb]%, ABO and Rhesus (Rh), blood sugar, bleeding time, clotting time, urine routine and microscopy) were ordered for all patients.

ÂÂ

USG of all the patients were done.

ÂÂ

Detailed informed consent of all the patients was obtained before taking up for any procedure.

ÂÂ

Hysteroscopy and diagnostic D&C were done for each of these patients.

ÂÂ

If indicated, hysteroscopic-guided curettings were also taken and sent for histopathological analysis.

ÂÂ

The procedures were done under total intravenous (IV) anesthesia in operation theater.

ÂÂ

The curettings were sent for histopathological examination. The findings at USG, D&C reports, hysteroscopy were compared with each other.

OBSERVATIONS AND RESULTS In the present study, panoramic hysteroscopy was performed using a 4 mm hysteroscope with 30˚fore oblique lens (Kalekar, India) in 50 patients of AUB followed by D&C. The curetted endometrium was sent for histopathological analysis.

Percentage (%)

20-29

30-39

40-49

50-60

30 20 8

0 Age groups

Figure 1. Age incidence of AUB.

Table 2. Duration of Symptoms Duration (in months)

No. of patients

Percentage (%)

1-3

3-6

6-12

>12

1-3 months Duration of symptoms

ÂÂ

The maximum patients suffered for a period between 3-6 months, 25 (50%). This was followed by 13 patients (26%) suffering for 6 months to 1 year. Ten patients (20%) suffered for 1-3 months and two patients (4%) suffered

No. of patients (%)

ÂÂ

The number of patients within the age of 20-29 years and 30-39 years were almost equal, 22 (44%) and 21 (42%), respectively. The youngest patient was 21 years old, and the eldest was 56 years old (Table 1 and Fig. 1).

3-6 months

6-12 months

>12 months

20 50 26 4 0

No. of patients (%)

Figure 2. Duration of symptoms.

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OBSTETRICS AND GYNECOLOGY Table 3. Symptoms at Presentation

NAD

No. of patients

Percentage (%)

Menorrhagia

Metrorrhagia

Polymenorrhea

Postmenopausal bleeding

Fiborid

40 No. of patients (%)

Symptoms

Polyps

Endometriosis

Adenomyosis

USG findings

Figure 4. Findings at ultrasound.

Menorrhagia

Metrorrhagia

Polymenorrhea

Postmenopausal bleeding

Table 5. Findings at Histopathology Findings 6%

46%

30%

No. of patients

Percentage (%)

Normal/sample inadequate

Endometrial hyperplasia

Endometrial atrophy

Endometritis

Normal Endometrial hyperplasia

18%

Figure 3. Common symptoms at presentation.

12%

Table 4. Findings at Ultrasound Symptoms

No. of patients

Percentage (%)

Fibroid uterus

Submucous

Subserosal

Intramural

Pedunculated

Polyp

Endometrial

Cervical

Endometritis

Adenomyosis

Noabnormality detected

for >12 months, and have resorted to various forms of supportive therapy (Table 2 and Fig. 2). Menorrhagia was the most common presenting symptom, reported in 23 (46%) patients. Polymenorrhea was the next most

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Endometrial atrophy Endometritis

44%

36%

Figure 5. Histopathology findings.

common symptom, reported in 15 (30%) patients. Nine patients (18%) complained of metrorrhagia and three patients (6%) suffered from postmenopausal bleeding (Table 3 and Fig. 3). Nineteen (38%) patients were diagnosed with fibroid uterus, of various types - submucous in 9 (18%) patients, intramural in eight (16%) patients and one patient (2%) each with subserosal and pedunculated fibroid. Thirteen (26%) patients were diagnosed with adenomyosis. Eight (16%) patients were diagnosed with polyps - 6 (12%) of which were endometrial and

OBSTETRICS AND GYNECOLOGY Table 6. Hysteroscopic Findings Findings

No. of patients Percentage (%)

Normal

Endometrial hyperplasia

Polyps

Fibroid

Endometrial atrophy

Endometritis

Normal

Polyp

Endometrial atrophy

Endometrial hyperplasia

Fibroid

Endometriosis

No of patients (%)

40 30 20 10 0

Figure 8. Hysteroscopic view of polyp.

38 22

20 14 2

Hysteroscopic findings

Figure 6. Hysteroscopic findings of the patients.

hyperplasia. Six (12%) patients had reports suggestive of endometrial atrophy. Four cases (8%) had findings suggestive of endometritis (Table 5 and Fig. 5). Eleven (22%) patients were found to have no abnormality of hysteroscopy. Nineteen (38%) patients were found to have endometrial hyperplasia on hysteroscopy. Ten (20%) patients were found to have fibroids. Seven (14%) patients had polyps, 2 (4%) patients had endometritis and 1 (2%) case was diagnosed with endometrial atrophy (Table 6 and Fig. 6). INTERPRETATION AND DISCUSSION The age group in this study was between 20-60 years and maximum incidence was found to be between the ages of between 30-39 years (44%), closely followed at 42% between ages of 40-49 years.

Figure 7. Hysteroscopic view of fibroid.

In a study conducted by Schwarzler a total of 104 patients with age varying from 26 to 79 years were evaluated.7 Tahir studied 400 women all above age of 35 years with maximum incidence between 40-50 years.8 Gianninoto performed diagnostic hysteroscopy in 512 women with complaints of AUB, age ranging from 38 to 80 years and commonest incidence was between 30-45 years.9 In the study by Panda et al, maximum age incidence was found between 35-45 years, which is in agreement with our study.10 Similarly, van Trotsenburg reported maximum age incidence between 41-50 years.11

two (4%) were cervical (Table 4 and Fig. 4). Twentytwo (44%) patients had reports termed to be normal. This also included the samples marked as inadequate for study, samples reported as cervical tissue only. Eighteen (36%) patients had reports of endometrial

Comparing the duration of complaints, it appears that maximum patients seek medical opinion after suffering for 3-6 months time (50%). The commonest presenting complaint in this series was menorrhagia 46%, followed by polymenorrhea (30%) and metrorrhagia (18%). Pandaâ&#x20AC;&#x2122;s series had 60% cases of menorrhagia followed

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OBSTETRICS AND GYNECOLOGY by polymenorrhagia and metrorrhagia, which is similar to our study.10 In this study, when a comparison is drawn between the findings of the three diagnosing modalities, the following results were found: ÂÂ

D&C revealed normal findings in 44% cases. This also included the reports of inadequate or incorrect samples, which does not help in reaching an accurate diagnosis.

ÂÂ

USG on the other hand revealed normal study in only 16% patients. But, this was proven wrong by the findings of hysteroscopy, which revealed normal findings in 22% cases.

ÂÂ

D&C reveals pathological abnormal reports in 56% cases, USG revealed a pathology in 84% cases and hysteroscopy shows abnormal findings in 78% cases.

A sample for histopathology was obtained from the cases, which showed normal reporting otherwise on D&C, but had some form of abnormality when directly viewed with the aid of a hysteroscope. This helped us to not leave out any patient without a definite diagnosis and accurate treatment was offered. These readings reveal that, hysteroscopy is a better mode of diagnosing a direct cause of AUB in most of the cases as compared to a D&C. Also USG can falsely lead to an overzealous diagnosis and hence wrong treatment may be offered. This is in agreement with other similar studies, which also prove that panoramic hysteroscopy is better than curettage in the evaluation of AUB.8,9 CONCLUSION This study reveals the superior ability of hysteroscopy in evaluating patients with AUB, when compared to D&C and USG. Hysteroscopy is the safe, reliable and quick procedure in diagnosis of cases with abnormal uterine bleeding with high sensitivity, specificity and negative predictive value (ACOG 2011, A-1 level evidence). It is pivotal in the present day gynecological practice to arrive at an accurate diagnosis and specially not to miss any precancerous finding. The chances that such a

lesion would be missed is rare, if we stick to the criteria for negative hysteroscopic view and usually no further investigations may be necessary. At the same time, enough stress shall be laid on the importance of endometrial histopathology for diagnosis of any such lesion especially in peri- or postmenopausal patients inspite of negative hysteroscopic view. REFERENCES 1. Awwad JT, Toth TL, Schiff I. Abnormal uterine bleeding in the perimenopause. Int J Fertil Menopausal Stud 1993;38(5):261-9. 2. Munro MG. Abnormal uterine bleeding in reproductive years. Part II: Medical management. J Am Assoc Gynecol Laparosc 2000;7:17-35. 3. The initial management of menorrhagia: Evidence based clinical guidelines - No. 1. Royal College of Obstetricians and Gynaecologists, 1998. 4. Park K. Textbook of Preventive and Social medicine. 19th edition, 2008. 5. Cohen MR, Dmowski WP. Modern hysteroscopy: diagnostic and therapeutic potential. Fertil Steril 1973;24(12):905-11. 6. Taneja P, Duggal BS. Hysteroscopy: past, present and future. Med J Armed Force India 2002;58:293-4. 7. Schwärzler P, Concin H, Bösch H, Berlinger A, Wohlgenannt K, Collins WP, et al. An evaluation of sonohysterography and diagnostic hysteroscopy for the assessment of intrauterine pathology. Ultrasound Obstet Gynecol 1998;11(5):337-42. 8. Tahir MM, Bigrigg MA, Browning JJ, Brookes ST, Smith PA. A randomised controlled trial comparing transvaginal ultrasound, outpatient hysteroscopy and endometrial biopsy with inpatient hysteroscopy and curettage. Br J Obstet Gynaecol 1999;106(12):1259-64. 9. Gianninoto A, Morana C, Campione C. Diagnostic hysteroscopy in abnormal uterine bleeding. Five-years’ experience. Minerva Ginecol 2003;55(1):57-61. 10. P anda A, Parulekar SV, Gupta A. Diagnostic hysteroscopy in abnormal uterine bleeding and histopathological correlation. J Obstet Gynaecol India 1999;49:74-6. 11. van Trotsenburg M, Wieser F, Nagele F. Diagnostic hysteroscopy for the investigation of abnormal uterine bleeding in premenopausal patients. Contrib Gynecol Obstet 2000;20:21-6.

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PEDIATRICS

Neonatal Bartter Syndrome Meetu Rawat Gupta*, Subandhu Gupta†, Anand S Vasudev‡, RN Srivastava‡

Abstract Bartter syndrome is characterized by hypokalemia, metabolic alkalosis, increased urinary excretion of sodium, potassium and chloride and normal blood pressure. A rare subset of the disorder occurs in the newborn period, which prompts us to report two such cases. Both showed satisfactory response to treatment with indomethacin.

Keywords: Neonatal Bartter syndrome, hypokalemic metabolic alkalosis

artter syndrome is an inherited renal tubular disorder characterized by hypokalemia, hypochloremic metabolic alkalosis, normal blood pressure with hyperreninemia and increased urinary loss of sodium, potassium and chloride. The neonatal form of Bartter syndrome is rare and clinically manifests with failure to thrive, polyuria and episodes of dehydration. We report two infants with neonatal Bartter syndrome, who had typical clinical features, but early diagnosis was not made. Both improved with administration of indomethacin and potassium supplements.

CASE REPORT

Case 1 A 15-month-old boy was referred with complaints of failure to thrive since birth. He was a term smallfor-gestational age (birth weight 1.8 kg) and was a product of nonconsanguineous marriage. Maternal polyhydramnios was detected in the 5th month of pregnancy. There was no history of birth asphyxia. He was exclusively breastfed for the first 3 months of life after which cow milk was given and by 5th month of life, complementary feeds were introduced, which were poorly tolerated. He showed poor oral acceptance for solids yet would consume liquids in large amounts

*Pediatric Registrar †Senior Resident ‡Senior Consultant Dept. of Pediatric Nephrology Indraprastha Apollo Hospitals, New Delhi Address for correspondence Dr Meetu Rawat Gupta 533, SFS Flats, C and D Block Shalimar Bagh, New Delhi - 88 E-mail: meetur2007@yahoo.com.

and pass urine frequently. He developed vomiting, around 2-3 times a day, nonbilious, nonprojectile, being partially relieved by antiemetics. The weight gain was poor (4.5 kg at 12 months). At age of 14 months, he developed fever with respiratory distress, needing hospital admission for 10 days and was treated with intravenous antibiotics. Metabolic alkalosis was detected and he was referred to this hospital. There was no history of child neglect or parental discordance. There was no history of loose stools, cyanotic spells, seizures, altered sensorium and focal neurological deficits. Examination showed weight 4 kg (expected 11.21 kg), length 60 cm (expected 79.4 cm) and head circumference 42 cm (<3rd centile). He had no dysmorphic features. The blood pressure was normal. Systemic examination was within normal limits and neurological examination did not disclose any localizing signs. Detailed laboratory evaluation showed hypochloremic metabolic alkalosis, hypokalemia, increased urinary losses of K+, Ca++ and raised aldosterone level (Table 1), confirming the diagnosis of Bartter syndrome. Ultrasound abdomen revealed bilateral medullary nephrocalcinosis (Fig. 1). The child was managed with indomethacin 2 mg/kg, potassium supplementation and supportive treatment along with dietary advice. On discharge, there was clinical and biochemical improvement with serum potassium of 4.2 mEq/L. On regular follow-up visit up to present age of 5 years, he has showed consistent gain in weight.

Case 2 A 7½-month-old baby boy, resident of Kabul, Afghanistan, presented with complaints of failure to thrive, cough and polyuria since 4 months. He was a product of second-degree consanguineous marriage born as a term appropriate-for-gestational age by vaginal delivery. There was maternal history

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PEDIATRICS Table 1. Laboratory Investigations of the 2 Cases Investigations

Case 1

Case 2

2.4 mEq/L

3 mEq/L

Serum calcium

10 mg/dL

7.9 mg/dL

Serum magnesium

3.3 mg/dL

1.6 mg/dL

Serum chloride

98 mEq/L

99 mEq/L

Serum potassium

Serum aldosterone

1,087.4 IU/L

7.6

7.46

Bicarbonate

40.7 mEq/L

28.17 mEq/L

Urine sodium

41 mEq/L

3,000 mEq/L

Urine potassium

9.9 mEq/L

2 mEq/L

Urine calcium

2.5 mEq/L

1.8 mEq/L

Urine creatinine

11.1 mg/dL

13 mg/dL

0.22

0.28

42 mEq/L

< 15 mEq/L

Urine calcium: creatinine ratio Urine chloride

Figure 1. Ultrasound abdomen revealed medullary nephrocalcinosis.

of polyhydramnios. There was no history of birth asphyxia. Family history was not significant. The child required frequent hospitalizations for persistent cough in Kabul and Pakistan. Investigations on blood had shown low Na+, K+, Cl-, Mg+ and a high HCO3-, aldosterone, PGE, renin along with metabolic alkalosis. Ultrasound abdomen showed hyperechogenic kidneys. The chest X-ray was normal. Nuclear scan was positive for gastroesophageal reflux. A provisional diagnosis of Bartter syndrome was made and he was referred to this hospital. On examination, his weight was 4.86 kg (expected 8.64 kg), length 62.5 cm (expected 69.5 cm) and head circumference 38 cm (<3rd centile). He had

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mild pallor and normal BP. Systemic examination was within normal limits. Laboratory investigations (Table 1) showed metabolic alkalosis and increased urinary excretion of K+ and Ca+. The chest X-ray and ultrasound abdomen were normal. Child was managed with indomethacin, potassium supplementation and supportive treatment and discharged in stable condition. On follow-up, he showed marked clinical and biochemical improvement. DISCUSSION The two patients we described had typical abnormalities of Bartter syndrome. Although, the typical features were present almost since birth, the diagnosis wasÂ delayed by several months. There was marked clinical improvement with initiation of indomethacin and potassium supplements. Bartter syndrome is an inherited renal tubulopathy, which may manifest during the neonatal period, infancy or childhood.1 The sodium potassium 2 chloride cotransporter NKCC2 or the luminal potassium channel ROMK causes neonatal Bartter syndrome, where tubular losses of sodium, potassium, chloride and water cause secondary hyperaldosteronism.1,3 Bhamkar and Gajendragadkar have recently described a case report on antenatal Bartter syndrome with sensorineural deafness.2 Gitelman syndrome however is a phenotypically related channelopathy instead of being a variant of Bartterâ&#x20AC;&#x2122;s syndrome, affecting sodium chloride cotransporter. NCCT present in the distal convoluted tubule. Linkage analysis and mutational studies have revealed defects in the gene encoding sodium chloride co-transporter NCCT.3 The neonatal variant is particularly uncommon. Antenatal features include polyhydramnios and premature delivery.4 Amniotic fluid shows consistently elevated chloride levels. After birth, rapid weight loss may occur.5-7 Lethargy and poor feeding often develop.8 Special facial features like triangular face, prominent forehead, large eyes, strabismus, protruding ears, drooping mouth exist as also sensorineural deafness, convulsions and increased susceptibility to infections.4 Metabolic alkalosis with hypokalemia occurs in the first week of life. Urine has low specific gravity with very high sodium, chloride and calcium levels while potassium is normal.8 However, after 1-3 weeks, the level of potassium in the urine rises with relatively less level of sodium than in the first week of life. Prostaglandin levels are high, both in blood and in urine.8,9 Hyperprostaglandin E2 is a secondary phenomenon

PEDIATRICS due to fluid and electrolyte loss and is suppressed by appropriate fluid and electrolyte replacement over a period of time. Serum renin and aldosterone levels are also very high and are important in establishing the diagnosis. Untreated infants fail to thrive and may die in a few days as a result of dehydration, poor feeding or severe electrolyte disturbance. Mild mental retardation is linked to delay in diagnosis and treatment.8 Therapeutic efforts should be directed to correct dehydration and electrolytic imbalance.10 The treatment of Bartter syndrome consists of supplementation of potassium (1-3 mEq/kg/day) and after 6-12 weeks of life, administration of indomethacin (2-3 mg/kg/ day).1,4 Ibuprofen (30 mg/kg/day) has similar effect, but indomethacin has been more widely used. The treatment results in striking clinical improvement although serum potassium levels may not increase to above 3.5 mEq/L. Potassium sparing diuretics and angiotensin-converting enzyme inhibitors have also been used.1 Prenatal diagnosis can be made by the high chloride content of the amniotic fluid and mutational analysis of genomic DNA extracted from cultured amniocytes.11 Bartter syndrome and other renal tubulopathies should be considered in an infant with no obvious cause of failure to thrive and unexplained polyuria. Early investigation and treatment should begin to prevent long-term side effects like growth failure, nephrocalcinosis and renal failure.

2. Bhamkar RP, Gajendragadkar A. Antenatal Bartter’s syndrome with sensorineural deafness. Indian J Nephrol 2009;19(1):23-6. 3. Dell KM, Avner ED. Bartter/Gitelman syndromes and other inherited tubular transport abnormalities. In: Nelson Textbook of Pediatrics. 18th edition, Kliegman RM, Jenson HB, Behrman RE, Stanton BF (Eds.), Saunders Publications: Philadelphia 2007:p.2201-2. 4. Kumar PS, Deenadayalan M, Janakiraman L, Vijayakumar M. Neonatal Bartter syndrome. Indian Pediatr 2006;43(8):735-7. 5. Bartter FC, Pronove P, Gill JR Jr, Maccardle RC. Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. Am J Med 1962;33:811-28. 6. Massa G, Proesmans W, Devlieger H, Vandenberghe K, Van Assche A, Eggermont E. Electrolyte composition of the amniotic fluid in Bartter syndrome. Eur J Obstet Gynecol Reprod Biol 1987;24(4):335-40. 7. Ohlsson A, Sieck U, Cumming W, Akhtar M, Serenius F. A variant of Bartter’s syndrome. Bartter’s syndrome associated with hydramnios, prematurity, hypercalciuria and nephrocalcinosis. Acta Paediatr Scand 1984;73(6): 868-74. 8. Proesmans W. Bartter syndrome and its neonatal variant. Eur J Pediatr 1997;156(9):669-79. 9. Amirlak I, Dawson KP. Bartter syndrome: an overview. QJM 2000;93(4):207-15.

REFERENCES

10. Proesmans W, Massa G, Vanderschueren-Lodeweyckx M. Growth from birth to adulthood in a patient with the neonatal form of Bartter syndrome. Pediatr Nephrol 1988;2(2):205-9.

1. Srivastava RN, Bagga A. Renal tubular disorders. In: Pediatric Nephrology. 4th edition, Srivastava RN, Bagga A, (Eds.), Jaypee Brothers Publishers: New Delhi 2005:p.278-9.

11. Proesmans W, Massa G, Vandenberghe K, Van Assche A. Prenatal diagnosis of Bartter syndrome. Lancet 1987;1(8529):394.

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Don’t Touch That Remote! Household Surfaces may Spread MRSA The homes of many children infected with methicillin-resistant Staphylococcus aureus (MRSA) may be environments in which MRSA strains live on common household surfaces, according to an article published online September 8 in JAMA Pediatrics. That was the case for almost half of the children with MRSA infections in a recent study, in which researchers found MRSA on bed linens, television remote controls and bathroom hand towels. Household pets also carried MRSA strains. Stephanie A. Fritz, MD, MSCI, from the Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, and colleagues conducted a study involving 50 children with active or recent (within 2 months) community-acquired MRSA infection.

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PEDIATRICS

Familial Hypercholesterolemia: Report of a Family Suprabha Shukla*, Dillip kumar Das†, Narayan Prasad Modi‡

Abstract We report a family, two sibling and mother, who developed corneal arcus and multiple skin lesions in form of xanthomas. The lesions appeared all over the body involving fingers, hands, elbows, knees, buttocks and feet. Laboratory studies showed total serum cholesterol level of >700 mg/dL; triglyceride level <150 mg/dL in all the cases. Father died few years back at a young age due to cardiac illness. Findings were consistent with homozygous familial hypercholesterolemia. In our country, incidence of hypercholesterolemia is not known. Only few case reports are there in the available literature.

Keywords: Hypercholesterolemia, corneal arcus, xanthomas

amilial hypercholesterolemia (FH) is caused by mutations in the low-density lipoprotein (LDL) receptor, which prevent its synthesis, reduce its appearance on the cell surface, or impair its ability to bind and internalize LDL. Elevated LDL cholesterol levels lead to the major complication of this condition: Premature atherosclerotic cardiovascular disease. Homozygous FH is a rare variant, occurring with a frequency of 1:1,000,000.1 We present a family of homozygote manifesting with corneal arcus and multiple xanthomas.

Table 1. Lipid Profile of the Family Members

Case report

xanthomas. One of the siblings (elder) had corneal arcus without vision abnormality. Systemic examination was normal in both siblings. Mother had also multiple tendinous xanthomas and corneal arcus. Father died at the age of 34 years from sudden cardiac arrest. Investigation of the both siblings and mother were done to arrive at a diagnosis. Complete blood count, liver, renal and thyroid function tests were normal. Chest X-ray, ECG, echocardiography of all three were normal. Lipid profile of the siblings and mother were done suspecting FH (Table 1). Biopsy of the skin lesion was done; this was suggestive of xanthoma.

We are reporting two male siblings of age 8 years and 6 years, born out of consanguineous marriage with history of xanthomatous lesions for 5 and 3 years, respectively. Anthropometry was normal in both the cases. Physical examination showed presence of subcutaneous yellow nodules and plaques over the knuckles, elbows, knee, buttock and umbilicus of size up to 5 cm in size and in some regions tended to coalesce, suggestive of xanthoma and having both tendinous and tuberous

*Senior Resident Dept. of Pediatrics SCB Medical College, Cuttack, Odisha †Assistant Professor Hi-Tech Medical College, Bhubaneswar, Odisha ‡Associate Professor Dept. of Pediatrics SCB Medical College, Cuttack, Odisha Address for correspondence Dr Suprabha Shukla C/o: Bijay Mohan Biswal House No. 14, Malha Sahi, Mangalabag, Cuttack, Odisha E-mail: suprabha.shukla@gmail.com

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Sibling 1 Sibling 2 Mother (8 years Mch) (6 years Mch) Total cholesterol (mg/dL)

728

744

820

Triglyceride (mg/dL)

128

136

146

LDL (mg/dL)

655

679

621

HDL (mg/dL)

VLDL (mg/dL)

With these presentations, diagnosis of familial homozygous hypercholesterolemia was considered as mother and siblings had corneal arcus and xanthoma and had very high LDL and total cholesterol with normal triglyceride level. But, due to unavailability of LDL receptor activity test, it could not be done. Both the siblings were treated with statin group of drugs (simvastatin 10 mg daily) and fat restricted diet. Now the family is under followup and the skin lesions flattening to some extent.

PEDIATRICS

Figure 1. Showing xanthoma in both hands, feet of mother and corneal arcus in both eyes.

Figure 2. Showing xanthoma in both the children and corneal arcus in one of the son.

Discussion Familial hypercholesterolemia is inherited as an autosomal dominant disorder. The gene for LDL receptor found in chromosome 19. It may be heterozygous or homozygous variety.2

and elevated LDL level (Fredrickson type 2) and occasionally in hypercholesterolemia associated with prolonged cholestasis.3,4

Homozygous FH is clinically characterized by cutaneous xanthomas, enlarged achilles tendons, atherosclerosis and corneal arcus, usually developing from early childhood.

Some patients with homozygous FH do not have cutaneous xanthomas but acquire tuberous or tendon xanthomas on the elbows, knees or achilles tendons as older children or adolescents.5 The absence of xanthomas in children does not exclude the diagnosis. Arcus cornea may be present to some degree. Total cholesterol levels are usually >500 mg/dL and can be as high as 1,200 mg/dL. The major complication of homozygous FH is accelerated atherosclerosis, which can result in clinical sequelae even in childhood. Homozygous FH children often have symptoms of vascular disease before puberty, but symptoms can be atypical or go unreported; sudden death is common.6

Tendinous xanthoma is asymptomatic slowly enlarging subcutaneous nodules attached to tendons, ligaments, fascia and periosteum with normal overlying skin. Extensor tendons of hands, feet and achilles tendon are involved more frequently. They are often found in association with severe hypercholesterolemia

A child with relatively normal triglycerides and a total cholesterol level >500 mg/dL with or without cutaneous or tendon xanthomas, should be suspected of having homozygous FH. Parents and other relatives should be screened for hypercholesterolemia. Obstructive liver disease and nephrotic syndrome should be excluded

The prevalence of heterozygotes is 1 in 500 in populations. Although plasma cholesterol level is increased 2- to 3-fold since birth, but they became symptomatic in 3rd-6th decade of life with tendon xanthoma and cardiovascular complications. Response to treatment in these patients is good.2

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PEDIATRICS in each case. The diagnosis is mainly made on clinical grounds but can be confirmed in specialized centers by obtaining a skin biopsy specimen and performing an assay of the LDL receptor activity on the skin fibroblasts.6 Early combination therapy with LDL apheresis, statins and cholesterol absorption inhibitors are advised in children with homozygous FH at the highest risk. Our patients were managed with statin group of drug. These patients need regular follow-up and evaluation for underlying cardiac complication. References 1. Rader DJ, Cohen J, Hobbs HH. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J Clin Invest 2003;111(12):1795-803.

2. van Aalst-Cohen ES, Jansen AC, de Jongh S, de Sauvage Nolting PR, Kastelein JJ. Clinical, diagnostic, and therapeutic aspects of familial hypercholesterolemia. Semin Vasc Med 2004;4(1):31-41. 3. Pandhi D, Grover C, Reddy BS. Type IIa hyperlipoproteinemia manifesting with different types of cutaneous xanthomas. Indian Pediatr 2001;38(5): 550-3. 4. Somwanshi PR, Agarwal NS. Homozygous familial hypercholesterolemia (le). Indian J Dermatol Venereol Leprol 2000;66(6):331-2. 5. Zech LA Jr, Hoeg JM. Correlating corneal arcus with atherosclerosis in familial hypercholesterolemia. Lipids Health Dis 2008;7:7. 6. William A. Neal. Nelson Textbook of Pediatrics. 19th edition, Elsevier 2011:p.473-4.

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No Long-term Harmful Effects on Sleep in Premature Infants Administered Caffeine Therapy for Apnea Caffeine therapy for apnea of prematurity has no long-term harmful effects on sleep or control of breathing, according to a new study of 201 preterm children assessed at ages 5-12, the first study in humans to examine the long-term effects of neonatal caffeine treatment on sleep regulation and ventilatory control. “Animal studies have suggested that administration of neonatal caffeine to premature infants, while improving survival and other outcomes, may have long-term detrimental effects on sleep and control of breathing during sleep,” said lead author Carole L. Marcus, MBBCh, of Children’s Hospital of Philadelphia. “In our prospective follow-up study of 201 premature infants who participated as infants in the randomized, double-blind, placebocontrolled Caffeine for Apnea of Prematurity study, we found no evidence of long-term detrimental effects of caffeine treatment on sleep duration or sleep apnea during childhood.” The findings were published online ahead of print publication in the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine.

EEG Might Improve Autism Diagnosis and Determine Severity NEW YORK (Reuters Health) - Measuring how fast the brain responds to sights and sounds using electroencephalography (EEG) might provide an objective way to classify children on the autism spectrum and may help diagnose the condition earlier, say researchers at Albert Einstein College of Medicine of Yeshiva University in the Bronx, New York. An estimated one in 68 US children has an autism spectrum disorder (ASD), according to the U.S. Centers for Disease Control and Prevention (CDC). There is wide variation in the symptoms of ASD, from mild social and communication difficulties to profound cognitive impairments.

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Surgery

Surgical Treatment of Obesity and Diabetes PG Raman

Abstract Surgery for obesity is the last option but it is the most effective. Resolution of comorbid diseases with obesity occurs depending upon the amount of weight loss, age of the patients, duration of comorbid disorders. After malabsorptive surgeries, patient has to be on life-long vitamin supplements. Various types of surgeries done in morbid obesity with their merits and demerits have been described in this review.

Keywords: Bariatric surgery, gastric banding, gastric bypass surgery, Roux-en-Y gastric bypass, complications, cardiovascular outcomes

urgery for obesity is the last option but it is the most effective. Life-long medical surveillance is needed to prevent micronutrient and vitamin deficiencies after surgery. Conservative treatment is less effective than bariatric surgery in terms of weight reduction.

Types of Weight-Loss Surgeries Malabsorptive

Restrictive

Jejunoileal bypass

Vertical banded gastroplasty

Biliopancreatic diversion and duodenal switch

Laparoscopic adjustable gastric band Gastric bypass

Criteria for selection for Bariatric Surgery Body mass index (BMI) - 35-40 kg/m2 with significant comorbid diseases or obesity with BMI >40 kg/m2; well-informed, motivated patient who understands and accepts risk of surgery; long-time commitment to lifestyle changes and follow-up; supportive social environment and absence of psychosis or depression are the usual criteria for selection for bariatric surgery. Laparoscopic adjustable gastric banding Widely practiced simple surgery with less complications and low mortality (0.05%).1 Weight is lost slowly but for prolonged period. It is a restrictive procedure, hence vitamin deficiency is not common as the gastrointestinal (GI) tract is intact. Folic acid deficiency has been seen due to different eating habits after surgery viz. taking less fruits, vegetables and whole-meal bread. Patient has to take 4-6 small feeds to avoid vomiting or intense pain usually occurs if one eats a heavy meal. Chances of reoperation are less, results are good. Complications of this surgery are

prolapse of gastric wall through the band with acute stromal obstruction and vomiting; devise erosion and devise malfunction. Laparoscopic gastric bypass SURGERY (RNY) Complex and major surgery for those whose BMI is over 40. Significant weight loss occurs in 18 months. There is evidence that surgery can help to achieve complete remission, especially in morbid obese patients with diabetes. It is not effective in type 2 diabetes mellitus (T2DM) with low BMI.2 Elderly patients with T2DM with a prolonged duration are less likely to achieve euglycemia at 12 months. Higher rates of remission is seen in diabetic patients with shorter duration. Complete remission was observed with BMI above 32.3 This surgery carries a mortality rate of 0.4. Roux-en-Y gastric bypass (RYGB) in women with polycystic ovarian syndrome is effective in alleviating symptoms.4

Mechanism of DM Control in RYGB Distal Bowel Hypothesis Ex-Professor and Head, Dept. of Medicine MGM Medical College, Indore, Madhya Pradesh Address for correspondence Dr PG Raman 72, Dhar Kothi, Indore, Madhya Pradesh E-mail: drpgraman@gmail.com

Nutrients reach the distal ileum within 5 minutes of ingestion of food and this stimulates the secretion of glucagon-like peptide-1 (GLP-1) by L cells located in this area.5

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Surgery Vertical Sleeve Gastrectomy (Laparoscopic Gastric Sleeve Resection)

Effect of Bariatric Surgery on Weight Loss (EWL)

Done in patients with BMI over 35. Involves removing a major portion of the stomach. Once done, this surgery is not reversible. It is a type of restrictive surgery. First described by Hess in 1988, it provides acceptable percentage of weight loss (70-80%). Late nutritional complications occur after this surgery.6 Main complications are diarrhea, hepatic failure, metabolic derangement, protein malnutrition, iron deficiency anemia, vitamin deficiency and metabolic bone diseases.

All types of surgery

61.2

Gastric banding

47.5

Gastric bypass Gastroplasty BPD/DS

61.2 68.2 70

Vertical Banded

Type of surgery

Gastroplasty7

A small pouch of stomach, is created with gastric banding (stomach stapling). Revisional surgery is needed in vertical banded gastroplasty (VBG) due to stomal stenosis, pouch enlargement or stapler dysfunction. Long-term weight loss and improved comorbidities occur. In 65% of cases, there is failure of surgery and need for revision and conversion surgeries.

Jejunoileal Bypass7 Jejunoileal bypass (JIB) is created by division of proximal jejunum distal to ligamentum teres, creating anastomosis to ileum 10 cm from ileocecal valve. Procedure creates short-gut syndrome. It becomes a malabsorptive procedure and results in weight loss. Patient develops nephrolithiasis, dental caries, renal failure, bypass enteritis, cirrhosis, hepatic failure, arthritis and severe metabolic deficiency. Risk of T2DM and coronary artery disease (CAD) risk factors reduced after gastric bypass and not after restrictive surgery. Benefits of Bariatric Surgery8 ÂÂ

Appetite decreases.

ÂÂ

Weight loss of 70% of excess of body weight* occurs.

ÂÂ

Seventy percent patients can stop blood pressure medication.

ÂÂ

Lipids come to normal in 70% of patients with dyslipidemia.

ÂÂ

Gastroesophageal reflux completely cured.

diseases

(GERD)

ÂÂ

Ninety percent of T2DM become euglycemic.

ÂÂ

Sleep apnea syndrome is completely cured.

ÂÂ

Long-lasting effect on weight and comorbidities.

*Percentage excess weight loss is - weight loss/total weight - normal weight (EWL). Expected EWL after bariatric surgery is 50-70%.

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Weight loss (EWL) %

Effect of Bariatric Surgery on Weight Loss and Amelioration of Comorbid Conditions7 Type of bariatric surgery

Weight loss Comorbid conditions after 2 yrs corrected after JIB

RYGB

30%

70% dyslipidemia

20%

70% hypertension

BPT

35%

Obstructive sleep apnea improved 90% T2DM reverted Gastroesophageal reflex cured in 100%

Hormonal Changes after Bariatric Surgery9 Hormone/Peptide

Ghrelin Postprandial PYY GLP-1 Enteroglucagon GIP C-peptide Adiponectin Leptin Resistin TNF-a

Changes seen Postbariatric surgery Increased Increased Increased Increased Decreased Decreased Increased Normalizes Decreased Decreased

IL-6 Decreased Plasminogen activator Decreased inhibitor-1 (PAI-1)

Obesity Increased Decreased Increased Decreased Increased Increased Decreased Increased Increased Increased Increased Increased

Long-term Complications of Bariatric Surgery10 Complications Reflux Vomiting Dysphagia Port-related problem Reoperation Conversion

LAGB 6% 42% 2% 10% 33% 10%

VBG 6% 41% 6% 0% 26% 63%

RYGB 0% 0% 4% 0% 8% 0%

Second reoperation

Surgery Comorbidity Resolution11 Resolution criteria

Gastric banding

Gastroplasty

Gastric bypass

BPD and DS

Total

47%

68%

62%

70%

61%

Mortality

0.1%

0.5%

1.1%

Resolution of DM

48%

72%

84%

99%

77%

Resolution of hyperlipidemia

50%

74%

97%

99%

79%

EWL

Hypertension

43%

69%

68%

83%

62%

Sleep apnea syndrome

95%

78%

80%

92%

86%

Resolution of fatty liver

Improved with all surgeries

Comorbidities Resolved or Improved after Laparoscopic Sleeve Gastrectomy12 Comorbidity

No. of Resolved Improved patients

Complications of Gastric Bypass ÂÂ

Anastomosis leakage, stricture and ulcer

ÂÂ

Dumping syndrome

ÂÂ

Nutritional deficiencies like iron, zinc, B1, vitamin B12 (due to lack of intrinsic factor)

Hypertension

119

97.5

98.3

Hyperlipidemia

96.3

ÂÂ

Pica develops due to iron deficiency

Depression

103

99.0

ÂÂ

Infection

Obstructive sleep apnea

97.3

ÂÂ

Hemorrhage

ÂÂ

GERD

113

99.1

Hypoparathyroidism due to inadequate calcium absorption

Arthritis

ÂÂ

Chronic joint pains

100

Hypochlorhydria leads to positive hydrogen breath test which is due to bacterial overgrowth in small bowel

Stress inconvenience

100

Asthma

100

ÂÂ

Muscle weakness due to protein deficit

ÂÂ

Psychological problems like depression

Comparison Between Lifestyle Modification and Bariatric Surgery13 Features

Lifestyle modification

Bariatric surgery

Cost Side effects

No cost Nil

Costly Vitamin deficiency and malabsorption with LGB, problems are less

Weight loss

Long-term results, moderate loss

Severe weight loss in short-time

Weight loss maintenance

Not maintained. Weight gain occurs after few years

Forever

Nutrient deficiency

Usually occurs

Effect on comorbid disorders

Mild-to-moderate

Marked amelioration to cure

Psychological problems Patients cooperation

No Can occur Needed, motivated to continue lifestyle modification for Not needed ever

Food habits

Must learn to eat healthy foods

Must learn to eat slowly and 4-6 small feeds to prevent vomiting and epigastric pain

Postoperative complications

Not applicable

Can develop. Needs revision or redo surgeries at times

Useful

In all age groups

Not much effective with low BMI, old age and with long-duration of comorbid disorders

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Surgery Systolic/diastolic BP, plasma glucose, glycosylated hemoglobin (HbA1C), total cholesterol and triglycerides, all above parameters decreased to normal after bariatric surgery. Clinically beneficial weight loss in patients with morbid obesity is possible with conservative nonsurgical interventions particularly residential intermittent program and weight loss camps. Despite much larger weight loss observed in surgical group, small weight losses of 5-15% achieved through lifestyle intervention can result in similar reduction in risk factors and resolution of comorbidities at one year.12

3. Huang CK, Shabbir A, Lo CH, Tai CM, Chen YS, Houng JY. Laparoscopic Roux-en-Y gastric bypass for the treatment of type II diabetes mellitus in Chinese patients with body mass index of 25-35. Obes Surg 2011;21(9):1344-9.

Cardiovascular Outcomes after Bariatric Surgery14-16

7. Strain GW, Gagner M, Pomp A, Dakin G, Inabnet WB, Hsieh J, et al. Comparison of weight loss and body composition changes with four surgical procedures. Surg Obes Relat Dis 2009;5(5):582-7.

Swedish obese subject study looked into cardiovascular outcomes after bariatric surgery. Patients were followed for 2-10 years. There were 2,000 surgically treated patients for obesity who were compared with 2,000 controlled subjects with lifestyle modification. In surgically treated cases, normalization of triglycerides, hyperglycemia of diabetes and hyperuricemia were seen. Despite reduction in disease-related deaths after gastric bypass, surgery risk of nondisease related deaths such as accidents and suicides increased as compared to control group due to psychological problems.17 Conclusion Various types of surgeries done in morbid obesity are described with their merits and demerits. Resolution of comorbid diseases with obesity occurs depending upon the amount of weight loss, age of the patients, duration of comorbid disorders. Low BMI patients may not fully benefit by these surgeries. After malabsorptive surgeries, patient has to be on life-long vitamin supplements and often after bariatric surgery, patient has to take small 4-6 frequent meals as large meal ingestion will lead to vomiting and intense abdominal pain. Even in restrictive surgery, patient needs folic acid supplementation. Hormonal changes after bariatric surgery are described. Bariatric surgery is compared with lifestyle modification. References

4. Eid GM, Cottam DR, Velcu LM, Mattar SG, Korytkowski MT, Gosman G, et al. Effective treatment of polycystic ovarian syndrome with Roux-en-Y gastric bypass. Surg Obes Relat Dis 2005;1(2):77-80. 5. Mason EE. The mechanisms of surgical treatment of type 2 diabetes. Obes Surg 2005;15(4):459-61. 6. Hess DS, Hess DW. Biliopancreatic diversion with a duodenal switch. Obes Surg 1998;8(3):267-82.

8. Jakobsen GS, Hofsø D, Røislien J, Sandbu R, Hjelmesaeth J. Morbidly obese patients - who undergoes bariatric surgery? Obes Surg 2010;20(8):1142-8. 9. Guldstrand M. Hormonal changes after bariatric surgery. Endocrine Abstracts 2010;22:S23. 10. Poitou Bernert C, Ciangura C, Coupaye M, Czernichow S, Bouillot JL, Basdevant A. Nutritional deficiency after gastric bypass: diagnosis, prevention and treatment. Diabetes Metab 2007;33(1):13-24. 11. Gluck B, Movitz B, Jansma S, Gluck J, Laskowski K. Laparoscopic sleeve gastrectomy is a safe and effective bariatric procedure for the lower BMI (35.0-43.0 kg/m2) population. Obes Surg 2010;21(8):1168-71. 12. Buchwald H, Avidor Y, Braunwald E, Jensen MD, Pories W, Fahrbach K, et al. Bariatric surgery: a systematic review and meta-analysis. JAMA 2004;292(14):1724-37. 13. Björvell H, Rössner S. A ten-year follow-up of weight change in severely obese subjects treated in a combined behavioural modification programme. Int J Obes Relat Metab Disord 1992;16(8):623-5. 14. Athyros VG, Tziomalos K, Karagiannis A, Mikhailidis DP. Cardiovascular benefits of bariatric surgery in morbidly obese patients. Obes Rev 2011;12(7):515-24. 15. Batsis JA, A. Romero-Corral, ML Collazo-Clavell, MG Sarr, V Somers, L Brekke, F. Lopez-Jimenez. Effect of bariatric surgery on cardiovascular risk factors and predicted effect on cardiovascular events and mortality in class II-III obesity. J Am Coll Cardiol 2006;47(4) (Suppl 1):358A.

1. Chapman AE, Kiroff G, Game P, Foster B, O’Brien P, Ham J, et al. Laparoscopic adjustable gastric banding in the treatment of obesity: a systematic literature review. Surgery 2004;135(3):326-51.

16. Sjöström L, Lindroos AK, Peltonen M, Torgerson J, Bouchard C, Carlsson B, et al; Swedish Obese Subjects Study Scientific Group. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004;351(26):2683-93.

2. Hussain A, Mahmood H, El-Hasani S. Can Roux-en-Y gastric bypass provide a lifelong solution for diabetes mellitus? Can J Surg 2009;52(6):E269-75.

17. Adams TD, Gress RE, Smith SC, Halverson RC, Simper SC, Rosamond WD, et al. Long-term mortality after gastric bypass surgery. N Engl J Med 2007;357(8):753-61.

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Unusual Presentation of Lipoma: A Case Report Suryapratap Singh

Abstract Lipoma is a benign tumor of adipose tissue and one of the most common benign neoplasms of the body. One type of soft tissue lesions of the oral cavity is lipoma. However, its occurrence in oral cavity is very rare. It accounts for 90-91% on the trunk and proximal portions of the extremities and only 1-4% of benign neoplasms of mouth affecting predominantly the buccal mucosa, floor of mouth and tongue. Here we present a case of an intraoral lipoma in a 30-year-old young male patient. After 3 years follow-up, the patients showed no signs of recurrence.

Keywords: Adipocytes, lipoma, oral, surgery

ipomas are the most common soft tissue mesenchymal neoplasms, with 15-20% of cases involving the head and neck region and only 1-4% affecting the oral cavity.1 A lipoma in the mouth is an asymptomatic slowly growing rare benign tumor of mesenchymal origin consisting of fat.1 It may present in various forms, as a sessile or pedunculated and single or lobulated tumor of variable size although mostly below 3 cm diameter, and generally surrounded by a fibrous capsule.

The first description of an oral lesion was provided in 1848 by Roux in a review of alveolar masses, where he referred to it as a ‘yellow epulis’.2 The etiology of lipoma is uncertain; some authors have suggested endocrine, traumatic and hereditary causes.1 The diagnosis is made by pathology of an incisional or excisional specimen. An important feature is that the tumor tends to float when placed in a 10% formaldehyde solution.1 Treatment consists of conservative surgical removal of the lipoma; recurrences are rare. The purpose of this study was to report a case of a patient with an oral lipoma; treatment consisted of surgical excision. The study includes a case report and a review of the literature.

mouth (Fig. 1). The patient informed that the tumor had grown within the last 6 months, which affected chewing and speech but was painless. An intraoral smooth well-defined sessile nodule of color similar to that of the surrounding mucosa was observed in the mucosa, a little above the alveolar ridge; it measured about 2.5 × 1.5 cm in size. Radiography revealed no bone involvement. An excision biopsy was carried out. Microscopically, the tissue revealed sheets of mature fat cells containing clear cytoplasm and eccentric nucleus, with no evidence of cellular atypia or metaplasia, which confirmed that it was a lipoma (Fig. 2). The tumor was placed in 10% formaldehyde, where it floated,

Case Report A 30-year-old male patient presented in Dept. of Surgery with a round nodule in the right region of the

Dept. of Traumatology Surgery and Neurosurgery Narayana Medical College and Hospital, Nellore, Andhra Pradesh Address for correspondence Dr Suryapratap Singh Dept. of Traumatology Surgery and Neurosurgery Narayana Medical College and Hospital, Nellore, Andhra Pradesh E-mail: dr_suryapratap_singh_tomar@yahoo.com

Figure 1. Preoperative presentation of intraoral lipoma at buccal mucosa.

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Surgery the normal body fat. If the caloric intake is reduced, lipoma does not decrease in size, although normal body fat may be lost. Lipomas are adipose mesenchymal neoplasms that rarely occur within oral cavity (1-4%). Lipids unavailable for metabolism7 coupled with the autonomous growth of a lipoma have rendered it to be a true benign neoplasm.8 Lipomas are slowly enlarging, with a soft, smoothsurface mass of the submucosal tissues. When it is superficial, there is a yellow surface discoloration. The lesion may be pedunculated or sessile and occasional cases show surface bosselation.4 Multiple lipomas of head and neck have been observed in neurofibromatosis, Gardner syndrome, encephalocraniocutaneous lipomatosis, multiple familial lipomatosis and proteus syndrome. Generalized lipomatosis have been reported to contribute to unilateral facial enlargement in hemifacial hypertrophy.9 Although its etiology is unknown, possible causes may include trauma, infection, chronic irritation and hormone alterations.5 In few cases of lipoma, rearrangement of 12q, 13q, 6p chromosomes have been observed.2 Figure 2. Histopathology of specimen showing fat cells.

suggesting fat content. The patient is currently being monitored and so far no recurrence has occurred. Discussion Lipomas of the mouth are benign tumors; they grow slowly, do not infiltrate other tissues, do not ulcerate and are painless. The cheek is the commonest site of occurrence in the intraoral cavity followed by tongue, floor of the mouth, buccal sulcus and vestibule, palate, lip and gingiva.3 This pattern corresponds closely to the quantity of fat deposit in the oral cavity. They are relatively rare in the mouth and the maxillofacial region.1,4 According to the literature, mouth lipomas are distributed evenly between sexes; most of these patients are aged over 40 years.5 The case is similar to other published reports, as the patient was aged 57 years. Generally, their prevalence does not differ with gender, although a predilection for men has been reported5 and they occur most often in patients older than 40 years.6 The pathogenesis of lipoma is uncertain, but they appear to be more common in obese people. However, the metabolism of lipoma is completely independent of

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Clinically, oral lipomas generally present as mobile, painless submucosal nodules, with yellowish tinge, as observed in our cases. In some cases, oral soft tissue lipomas can present as a fluctuant nodule. Because of these clinical features, other lesions, such as oral dermoid and epidermoid cysts and oral lymphoepithelial cysts must be considered in the differential diagnosis of oral lipomas.10 Also, most oral lymphoepithelial cysts are found on the floor of the mouth, soft palate and mucosa of the pharyngeal tonsil,11 which are uncommon sites for oral lipomas. Oral dermoid and epidermoid cysts also present as submucosal nodules and, typically, occur on the midline of the floor of the mouth.12 However, oral dermoid and epidermoid cysts can occur in other locations of oral mucosa. Because an oral lipoma can occasionally present as a deep nodule with normal surface color, salivary gland tumors and benign mesenchymal neoplasms should also be included in the differential diagnosis.13 Definitive diagnosis depends on correlation between the histological and clinical features.14 The histopathology remains the gold standard in the diagnosis of lipoma. Lipomas are not very different in microscopic appearance from the surrounding fat. Like fat, they are composed of mature fat cells, but the cells vary slightly in size and shape and are somewhat larger, measuring up to 200 mm in diameter. Subcutaneous

Surgery lipomas are usually thinly encapsulated and have distinct lobular patterns. Deep-seated lipomas have a more irregular configuration, largely depending on the site of origin. All are well-vascularized, but under normal conditions, the vascular network is compressed by the distended lipocytes and is not clearly discernible. Lipomas are occasionally altered by the admixture of other mesenchymal elements that comprise an intrinsic part of the tumor. The most common element is fibrous connective tissue, which is often hyalinized and may or may not be associated with the capsule or the fibrous septa. Lipomas with these features are often classified as fibrolipomas.15 Quite often; however, lesional fat cells are seen to ‘infiltrate’ into surrounding tissues, perhaps producing long thin extensions of fatty tissue radiating from the central tumor mass. When located within striated muscle, this infiltrating variant is called intramuscular lipoma (infiltrating lipoma), but extensive involvement of a wide area of fibrovascular or stromal tissues is best termed as lipomatosis. Occasional lesions exhibit excess numbers of small vascular channels (angiolipoma), a myxoid background stroma (myxoid lipoma, myxolipoma) or areas with uniform spindle-shaped cells interspersed among normal adipocytes (spindle cell lipoma). When spindle cells appear somewhat dysplastic or mixed with pleomorphic giant cells with or without hyperchromatic enlarged nuclei, the term ‘pleomorphic lipoma’ is applied. When the spindle cells are of smooth muscle origin, the term myolipoma may be used. It is called angiomyolipoma when the smooth muscle appears to be derived from the walls of arterioles. Rarely, chondroid or osseous metaplasia may be seen in a lipoma which is described as chondroid lipoma, osteolipoma or ossifying lipoma. On occasions, lipomas of the buccal mucosa cannot be distinguished from a herniated buccal fat pad, except by the lack of a history of sudden onset after trauma. Otherwise, lipomas of the oral and pharyngeal region are not difficult to differentiate from other lesions, although spindle cell and pleomorphic types of lipoma must be distinguished from liposarcoma.14 Most of these microscopic variations do not affect the prognosis, which is usually good.16 The treatment of oral lipomas, including all the histological variants is simple surgical excision. Although the growth of oral lipomas is usually limited, they can reach great dimensions, interfering with speech and mastication and reinforcing the need for

excision.17 Surgical excision is the ideal treatment with rare recurrence as we did in our case. Conclusion Presented in this report is a case of intraoral lipoma in a 30-year-old male. In referencing the literature to date, this type of case has been rarely documented. Solitary lipomas have enthused little interest in the past and have largely been ignored in the literature. The reason is that the most lipomas grow insidiously and cause few problems other than those of a localized mass. Approximately 15-20% of lipoma occurs in the head and neck region. Among the reported intraoral lipomas, 50% occur in the buccal mucosal region. Surgical excision is the ideal treatment with excellent outcome; however, complete resection should be emphasized as this is the key factor to avoid recurrence. It is therefore important to diagnose the lesion correctly in the physical examination and histopathology to establish the prognosis. Healthcare professionals need to understand this disease to treat it adequately. References 1. F regnani ER, Pires FR, Falzoni R, Lopes MA, Vargas PA. Lipomas of the oral cavity: clinical findings, histological classification and proliferative activity of 46 cases. Int J Oral Maxillofac Surg 2003;32(1):49-53. 2. Rajendran R. Shafer’s Oral Pathology. 5th edition, Elsevier: Amsterdam 2006:p.194-5. 3. de Visscher JG. Lipomas and fibrolipomas of the oral cavity. J Maxillofac Surg 1982;10(3):177-81. 4. Cawson RA, Binnie WH, Speight PM, Barrett AW. Lucas’s Pathology of Tumors of The Oral Tissues. 4th edition, Churchill Livingstone: New York 1984:p.176-9. 5. Furlong MA, Fanburg-Smith JC, Childers EL. Lipoma of the oral and maxillofacial region: Site and subclassification of 125 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004;98(4):441-50. 6. Epivatianos A, Markopoulos AK, Papanayotou P. Benign tumors of adipose tissue of the oral cavity: a clinicopathologic study of 13 cases. J Oral Maxillofac Surg 2000;58(10):1113-7; discussion 1118. 7. Vindenes H. Lipomas of the oral cavity. Int J Oral Surg 1978;7(3):162-6. 8. M iles DA, Langlais RP, Aufdemorte TB, Glass BJ. Lipoma of the soft palate. Oral Surg Oral Med Oral Pathol 1984;57(1):77-80. 9. Lawoyin JO, Akande OO, Kolude B, Agbaje JO. Lipoma of the oral cavity: clinicopathological review of seven cases from Ibadan. Niger J Med 2001;10(4):189-91.

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Surgery 10. A navi Y, Gross M, Calderon S. Disturbed lower denture stability due to lipoma in the floor of the mouth. J Oral Rehabil 1995;22(1):83-5.

14. Gnepp DR. Diagnostic Surgical Pathology of the Head and Neck. 1st edition, Saunders: Philadelphia 2010:p.192.

11. F laitz CM. Oral lymphoepithelial cyst in a young child. Pediatr Dent 2000;22(5):422-3.

15. Weiss SW, Goldblum JR. Enzinger and Weiss’s Soft Tissue Tumors. 5th edition, Mosby: Philadelphia 2007: p.571-639.

12. Longo F, Maremonti P, Mangone GM, De Maria G, Califano L. Midline (dermoid) cysts of the floor of the mouth: report of 16 cases and review of surgical techniques. Plast Reconstr Surg 2003;112(6):1560-5. 13. Tan MS, Singh B. Difficulties in diagnosing lesions in the floor of the mouth - report of two rare cases. Ann Acad Med Singapore 2004;33(4 Suppl):72-6.

16. Neville B, Damm DD, Allen CM, Bouquot J. Oral and Maxillofacial Pathology. Saunders: Philadelphia 2008:p.523-4. 17. Chidzonga MM, Mahomva L, Marimo C. Gigantic tongue lipoma: a case report. Med Oral Patol Oral Cir Bucal 2006;11(5):E437-9.

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Tinnitus - American Academy of Otolaryngology - Head and Neck Surgery Foundation Clinical Practice Guideline The American Academy of Otolaryngology - Head and Neck Surgery Foundation has released the first ever mutlidisciplinary, evidence-based clinical practice guideline to improve the diagnosis and management of tinnitus, the perception of sound - often ringing - without an external sound source. The guideline was published in the journal Otolaryngology - Head and Neck Surgery. “Tinnitus affects 10-15% of adults in the United States. It is the most common service-related disability among our military veterans. Yet despite its prevalence and effect on quality of life, prior to this there weren’t any evidencebased guidelines about managing tinnitus,” said Sujana S. Chandrasekhar, MD, a co-author of the guideline.

Strict Blood Sugar Control after Heart Surgery may not be Necessary, Regardless of Diabetes Status Study results may encourage hospitals to consider more liberal blood sugar control policies. Patients undergoing coronary artery bypass grafting (CABG) surgery may not have to follow a strict blood sugar management strategy after surgery, according to a study in the October 2014 issue of The Annals of Thoracic Surgery.

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Around the Globe

News and Views ÂÂ Patients reporting memory problems appear to

be at increased risk for subsequent mild cognitive impairment (MCI) or dementia, suggests a new study published online September 24 in Neurology.

ÂÂ The North American Menopause Society (NAMS)

has published clinical care recommendations to address the multiple issues facing women in midlife. The recommendations are published in the October issue of Menopause. The recommendations cover key issues specific to menopause including vasomotor symptoms, osteoporosis and vulvovaginal health, as well as more general issues related to sexual function, cognition, cardiovascular health, thyroid disease and cancers.

ÂÂ The “laser-Doppler-imager (LDI) flare” may serve as

a new method for detecting early small-nerve-fiber changes in people with diabetes, suggest the first year of results from a prospective study presented recently at Neurodiab, the annual meeting of the Diabetic Neuropathy Study Group of the European Association for the Study of Diabetes.

ÂÂ Positron emission tomography combined with

fludeoxyglucose F 18 (FDG-PET) seems less accurate for diagnosing lung disease in areas where infectious lung disease is endemic, suggested a new meta-analysis published in the September 24 issue of JAMA. The pooled sensitivity of FDG-PET for diagnosing lung cancer was 89%, and the pooled specificity was 75%. Researchers noted that in the 10 studies reporting endemic disease, the pooled specificity was lower (54%) than in the remaining 60 studies not reporting endemic disease (78%).

ÂÂ The US Food and Drug Administration (FDA)

has approved apremilast for treating patients with moderate-to-severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

ÂÂ Differentiating

chikungunya from dengue: Chikungunya and dengue are both acute febrile illnesses characterized by fever, myalgia and lethargy. Some patients may also have maculopapular rash, nausea, vomiting and headache. Distinguishing features of chikungunya include potentially debilitating bilateral polyarthralgia and, in some cases, arthritis. Although these signs and symptoms may assist in differentiating dengue and chikungunya, clinicians

should include both illnesses in their differential diagnosis of patients with acute febrile illness. Such patients should also be evaluated for other serious conditions, such as malaria, leptospirosis and other bacterial infections. ÂÂ Antibiotic

use was independently associated with a dramatic risk of recurrent Clostridium difficile infection in an out-patient cohort (Aliment Pharmacol Ther 2014;40(5):518-522). It is important to avoid unnecessary systemic antibiotics in patients with C. difficile infection and patients with ongoing antibiotic use should be monitored closely for recurrent infection.

ÂÂ Recent studies have suggested that gut bacteria

play a fundamental role in diseases such as obesity, diabetes and cardiovascular disease. Data are accumulating in animal models and humans suggesting that obesity and type 2 diabetes (T2D) are associated with a profound dysbiosis. Butyrateproducing bacteria such as Roseburia intestinalis and Fecalibacterium prausnitzii concentrations are lower in T2D subjects.

ÂÂ Most treatment strategies used to treat acute

venous thromboembolism (VTE) appear to be as safe and effective as the currently recommended combination of low-molecular-weight heparin (LMWH) plus a vitamin K antagonist; however, they are not interchangeable, suggests a large network analysis published recently in JAMA.

ÂÂ The American Association for Thoracic Surgery

(AATS) has issued new guidelines to help prevent the development of atrial fibrillation (AF) during or after surgery and for the clinical management of patients in whom AF or atrial flutter develops. The recommendations are published September 23 in the Journal of Thoracic and Cardiovascular Surgery.

ÂÂ In most children whose epilepsy started following a

standard vaccination, there appears to be a genetic or structural cause and about one-third of cases of epilepsy triggered by a vaccine are relatively benign, suggests a new study published online in Pediatrics.

ÂÂ Systemic steroids increase the risk of post-

tonsillectomy bleeding in children, but not in adults, suggests a new Japanese study published online in JAMA Otolaryngology – Head & Neck Surgery.

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Around the Globe Researchers noted that the rate of reoperation for hemostasis was significantly higher in the steroid group than in the control group (1.6% vs. 0.9%). ÂÂ Patients with chronic lower back pain and opioid

addiction show regional brain activity on MRI that corresponds with disease severity and changes in behavioral therapy, compared with patients who do not receive the therapy, suggests a new study presented at the American Academy of Pain Management (AAPM) 25th Annual Clinical Meeting.

ÂÂ Patients with hemorrhagic stroke who received

a statin while in the hospital appeared to have better survival rates and were more likely to be discharged home or to a rehabilitation center as compared to those who did not get a statin while an inpatient, suggested a new study published online September 22 in JAMA Neurology.

ÂÂ Results of a modeling-based study suggest that

routine MRI is not a cost-effective diagnostic tool in the evaluation of idiopathic olfactory loss. The findings were published in JAMA Otolaryngology Head & Neck Surgery.

ÂÂ A new population-based study from 5 countries

has noted that overall, new cancer incidence appears to be about the same for type 1 diabetes as for type 2 diabetes patients. The findings also possibly exclude any major carcinogenic effect of insulin in type 1 diabetes patients. The findings were presented at the European Association for the Study of Diabetes 2014 Meeting.

ÂÂ In patients with neuromyelitis optica spectrum

disorder, treatment with the immunosuppressant mycophenolate mofetil appears to reduce the frequency of relapse, stabilizes or improves disabilities and is well tolerated, suggests a new retrospective study published online in JAMA Neurology.

ÂÂ New research from the UK has found that heart

attack patients have a greater chance of dying after discharge from the hospital if they miss even one component of their after-care. Heart attack patients had a 46% higher chance of dying within a month, and a 74% chance of dying within a year of discharge, if any one of the elements of care is missed. The findings were published in the European Heart Journal: Acute Cardiovascular Care.

ÂÂ A daily small serve of dairy food could possibly

reduce the risk of heart disease or stroke, even in communities where such foods are not traditionally

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part of the diet, suggests a new study published in the Journal of the American College of Nutrition. Study authors noted that increased dairy consumption translated into lower risks of mortality from cardiovascular disease. ÂÂ Data from children with severe asthma have

shown that findings from adults cannot be translated to children and that steroid-resistant eosinophilic inflammation appears central to the pathogenesis of paediatric disease. Age-appropriate experimental models and use of airway samples from children are critical to understanding the underlying mechanisms and identifying novel therapeutic targets (Curr Opin Allergy Clin Immunol 2014;14(2):143-148).

ÂÂ In-flight pediatric deaths higher among lap infants.

The article quoted a study that found that 90% of airline deaths occurred in children under age 2 years, and it recommended that parents should reconsider bringing little ones on vacations that involve flying to various destinations (Science World Report August 4, 2014).

ÂÂ Depression and illness: Chicken or egg? When

depression strikes, doctors usually probe what’s going on in the mind and brain first. But it’s also important to check what’s going on in the body, since certain medical problems are linked to mood disturbances. In fact, medical illnesses - and medication side effects - may be behind nearly 10-15% of all cases of depression.

ÂÂ According to results of a retrospective study, the

presence of five or more cerebral microbleeds was associated with an increased mortality risk from all-cause (HR 1.99, p = 0.040) and ischemic stroke (HR 3.39, p = 0.007) after adjusting for age, sex and other significant risk factors for stroke death, wrote Tae-Jin Song, MD, of Yonsei University College of Medicine in Seoul and colleagues.

ÂÂ An FDA advisory committee handed a potential

setback to proponents of “low-T” treatment by overwhelmingly recommending a tightening of label indications for testosterone and renewed efforts to curb off-label use.

ÂÂ Eating a diet high in salt may increase the risk

of rheumatoid arthritis among smokers, suggests a new study. Smokers were more than twice as likely as subjects with a low-salt diet to develop the condition. The study was published online in Rheumatology.

Around the Globe ÂÂ The US Food and Drug Administration (FDA) has

approved dulaglutide, as a once-weekly injection for the treatment of type 2 diabetes. The approval was based on 6 clinical trials involving a total of 3,342 patients who received the drug.

mentioned by these patients in everyday life. The study was published online September 15 in Arthritis & Rheumatism. ÂÂ Magnetic resonance imaging (MRI) findings can

be used to predict radiographic progression of hand osteoarthritis, suggests a study published online in the Annals of Rheumatic Diseases. MRI visualization at baseline of synovitis, bone marrow lesions and joint space narrowing predicted progression of joint space narrowing.

ÂÂ Left ventricular ejection fraction (LVEF) increased

and symptoms improved considerably in patients initially with atrial fibrillation (AF) and LVEF <35% with severe heart failure who underwent catheter ablation for their arrhythmia, reported a small single-center series with follow-ups averaging 27 months. The data were presented at the Heart Failure Society of America (HFSA) 18th Annual Scientific Meeting. real-world comparison of clopidogrel vs prasugrel in about 12,000 acute coronary syndrome (ACS) patients undergoing PCI revealed no significant differences in the rate of major adverse cardiovascular events (MACE) between the two antiplatelet agents, suggested a new study presented at the TCT 2014.

ÂÂ Two-year

results from a head-to-head trial comparing the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin with the sulfonylurea glimepiride as second-line therapy after metformin in patients with type 2 diabetes has shown that empagliflozin was better than glimepiride. The findings were presented at the European Association for the Study of Diabetes 2014 Meeting.

ÂÂ A

ÂÂ Percutaneous patent foramen ovale closure did

not significantly reduce the number of monthly migraines days compared with medical treatment. But PFO closure did reduce the number of monthly migraine with aura days compared with medical treatment, according to the Percutaneous Closure of Patent Foramen Ovale in Migraine with Aura (PRIMA) study, David Hildick-Smith, MD, director of the Cardiac Research Unit at Brighton and Sussex University Hospitals in Brighton, England, said at the Transcatheter Cardiovascular Therapeutics meeting.

ÂÂ Moderate to vigorous aerobic exercise in the

morning could possibly reduce the symptoms of attention-deficit/hyperactivity disorder (ADHD) in young children at risk for the illness, suggests a new study published online in the Journal of Abnormal Child Psychology.

ÂÂ Newborns exposed to azithromycin in the first

6 weeks of life have a significantly increased risk of developing hypertrophic pyloric stenosis, suggests a new study presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).

ÂÂ Beta-blockers are of zero benefit in patients with

heart failure and reduced ejection fraction if they also have atrial fibrillation. Dr Dipak Kotecha (University of Birmingham, UK) presented the analysis Tuesday during the final clinicaltrial-update session of the European Society of Cardiology (ESC) 2014 Congress published simultaneously in The Lancet.

ÂÂ The artificial sweeteners aspartame, sucralose

and saccharin cause blood glucose abnormalities in some humans, suggested an article published online September 17 in Nature.

ÂÂ Mindfulness-based

stress reduction (MBSR) appears to be a safe and effective option for decreasing the effect of migraine headache and can be carried out while patients continue to take migraine medication, suggested a pilot study published online in the journal Headache.

ÂÂ Two polymer-based, nonsystemic oral agents that

ÂÂ Brain scans of patients with fibromyalgia revealed

that they processed nonpainful stimuli, such as sound and touch, differently as compared to the brains of people without the disorder. This could possibly explain the hypersensitivity to sensations

sequester potassium in the gastrointestinal tract appear to prevent or treat hyperkalemia in patients with heart failure. It was noted that they could lower serum potassium levels without inducing hypokalemia and help maintain potassium levels in the normal range in patients with heart failure taking guidelines-recommended renin-angiotensinaldosterone (RAAS)-inhibiting medications. The findings were presented at the Heart Failure Society of America (HFSA) 2014 Scientific Meeting.

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EXPERT VIEW

How to Manage Hypertension in a Patient with Acute Heart Attack? KK Aggarwal*, RK Arora

n patients with acute myocardial infarction (AMI), the prevalence of antecedent hypertension varies from 31% to 59%.1,2 However, it is not clear whether previously known hypertensive patients have an increased rate of adverse outcomes after AMI including stroke, heart failure and cardiovascular death.3 Conversely, in non-ST elevation myocardial infraction (NSTEMI), hypertension is an independent factor for major short- and long-term cardiac adverse outcome.4 In a patient presenting with AMI and severe hypertension, the reduction of blood pressure (BP) should not be abrupt and a gradual reduction over a period of 24-48 hours is recommended, so that further myocardial or brain ischemia is avoided.5 The appropriate treatment should include the initiation of intravenous nitrates, with intravenous labetalol, sodium nitroprusside and/or nicardipine as alternatives, especially in very severe hypertension or hypertensive emergencies. Sublingual nifedipine, which has usually been considered as a firstline drug, should be avoided, in view of the negligible oral absorption and unpredictable hypotensive effects.5 In the majority of patients presenting as an emergency with AMI and hypertension without signs of other acute target organ damage, hypertension does not necessarily represent an acute major threat. Treatment should be aimed at relieving symptoms, protecting the ischemic but potentially viable myocardial tissue and reducing mortality. BP should be reduced to <160/110 mmHg before administration of thrombolysis, although if available, primary angioplasty is an option for reperfusion in patients with high BP and/or the perceived risk of stroke if thrombolysis is unacceptable.5 Oral or intravenous b-adrenoceptor blockers lower the BP within hours. They also have important antiischemic effects, so that they should be considered as first-line therapy in patients with myocardial infarction (MI), in the absence of contraindications.5 These drugs exert a protective effect on the ischemic

*Senior Physician and Cardiologist Moolchand Medcity, New Delhi

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myocardial tissue by reducing oxygen demand by 1530%. Moreover, the b-blockers have antiarrhythmic properties and cause favorable shunting of blood away from nonischemic to ischemic regions. In the presence of chronic ischemia, b-blockers can also increase the ejection fraction, particularly during exercise and improve left ventricular (LV) function.5 Angiotensin-converting enzyme (ACE) inhibitors are recommended for use in all patients after MI. Two major trials, the European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) and the Heart Outcomes Prevention Evaluation (HOPE) study, showed the cardioprotective effects of ACE inhibitors in hypertensive coronary heart disease (CHD) patients.6-9 In the EUROPA study, 12,218 patients were randomized to treatment with an ACE inhibitor (perindopril) or placebo. Individuals in the perindopril group had significantly less MI, cardiovascular system (CVS) death or cardiac arrest.6 The HOPE study involved 9,297 patients with CVS risk factors, who were randomized to ramipril or placebo. Approximately half of the study population had hypertension. Ramipril therapy was associated with small (3/2 mmHg) reduction in BP but significant reduction in CVS death, stroke and MI.7,8 These cardioprotective effects were initially thought to be independent of BP control, until a subgroup analysis of the HOPE trial revealed a significant reduction in 24-hour ambulatory BP with ramipril that was not found in the main trial that measured only office BP.9 ACE inhibitors are indicated for all hypertensive patients with AMI who have no contraindications, especially if there is associated depressed LV systolic function (left ventricular ejection fraction [LVEF] <40%).10,11 From the trials available in patients presenting with AMI with hypertension, calcium channel blockers like verapamil and probably diltiazem can be used as thirdline drugs, after b-blockers, ACE inhibitor and nitrates, for treating hypertension during an AMI, if LV function is preserved.

EXPERT VIEW of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebocontrolled, multicentre trial (the EUROPA study). Lancet 2003;362(9386):782-8.

References 1. Willich SN, Müller-Nordhorn J, Kulig M, Binting S, Gohlke H, Hahmann H, et al; PIN Study Group. Cardiac risk factors, medication, and recurrent clinical events after acute coronary disease; a prospective cohort study. Eur Heart J 2001;22(4):307-13. 2. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, et al; INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364(9438):937-52. 3. Thune JJ, Signorovitch J, Kober L, Velazquez EJ, McMurray JJ, Califf RM, et al. Effect of antecedent hypertension and followup blood pressure on outcomes after high-risk myocardial infarction. Hypertension 2008;51(1):48-54. 4. Dumaine R, Gibson CM, Murphy SA, Southard M, Ly HQ, McCabe CH, et al; Thrombolysis in Myocardial Infarction (TIMI) Study Group. Association of a history of systemic hypertension with mortality, thrombotic, and bleeding complications following non-ST-segment elevation acute coronary syndrome. J Clin Hypertens (Greenwich) 2006;8(5):315-22. 5. Lip GY, Lydakis C, Beevers DG. Management of patients with myocardial infarction and hypertension. Eur Heart J 2000;21(14):1125-34. 6. Fox KM. EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril in reduction

7. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342(3):145-53. 8. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342(18):1376. 9. Svensson P, de Faire U, Sleight P, Yusuf S, Ostergren J. Comparative effects of ramipril on ambulatory and office blood pressures: a HOPE Substudy. Hypertension 2001;38(6):E28-32. 10. Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systematic overview of individual data from 100,000 patients in randomized trials. ACE Inhibitor Myocardial Infarction Collaborative Group. Circulation 1998;97(22):2202-12. 11. Flather MD, Yusuf S, Køber L, Pfeffer M, Hall A, Murray G, et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet 2000;355(9215):1575-81.

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mediLAW

Real Consent and not Informed Consent Applicable in India (Part II) KK Aggarwal

What is Bolam’s test? “The stringent standards regarding disclosure laid down in Canterbury, as necessary to secure an informed consent of the patient is not accepted in the English courts. In England, the standard applicable is popularly known as the Bolam’s test, first laid down in a trial relating to negligence of a medical practitioner (Bolam v. Friern Hospital Management Committee [1957] 2 All.E.R. 118). While instructing the Jury, it was stated thus: i.

A doctor is not negligent, if he has acted in accordance with a practice accepted as proper by a responsible body of medical men skilled in that particular art. Putting it the other way round, a doctor is not negligent, if he is acting in accordance with such a practice, merely because there is a body of opinion that takes a contrary view. At the same time, that does not mean that a medical man can obstinately and pig-headedly carry on with some old technique if it has been proved to be contrary to what is really substantially the whole of informed medical opinion.

ii.

When a doctor dealing with a sick man strongly believed that the only hope of cure was submission to a particular therapy, he could not be criticized if, believing the danger involved in the treatment to be minimal, did not stress them to the patient.

iii.

In order to recover damages for failure to give warning the plaintiff must show not only that the failure was negligent but also that if he had been warned he would not have consented to the treatment.”

Thus, a doctor would be judged as ‘negligent’ if he does not follow acceptable norms of practice using prevalent techniques, does not take due care in choosing the treatment/therapy for cure i.e., takes risks which are

Senior Physician and Cardiologist, Moolchand Medcity, New Delhi Member, Ethics Committee, Medical Council of India

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high and not just minimal, without even stressing and making the patient aware of it. Furthermore, if the patient, when asked to consent would have declined from consenting to a particular treatment administered, then the doctor has violated the legal obligation of seeking real consent as per Bolam’s law. Under the doctrine of ‘real consent’, the doctor must warn his patient of the risks inherent in the recommended treatment and the terms of giving such warning must be in accordance with the practice accepted at that time as considered proper by a responsible body of medical opinion. This is Bolam’s law or ‘Real Consent’ (Indian J Radiol Imaging 2008;18(3):195-7).

What is adequate information? For the patients to play a significant role in decisionmaking they must have adequate information. In the Samira Kohli vs. Dr. Prabha Manchanda and Ors. I (2008) CPJ 56 (SC), the Hon’ble Supreme Court of India observed: “32. ii: The ‘adequate information’ to be furnished by the doctor (or a member of his team) who treats the patient, should enable the patient to make a balanced judgment as to whether he should submit himself to the particular treatment as to whether he should submit himself to the particular treatment or not. This means that the Doctor should disclose (a) Nature and procedure of the treatment and its purpose, benefits and effect; (b) alternatives if any available; (c) an outline of the substantial risks and (d) adverse consequences of refusing treatment. But, there is no need to explain remote or theoretical risks involved, which may frighten or confuse a patient and result in refusal of consent for the necessary treatment. Similarly, there is no need to explain the remote or theoretical risks of refusal to take treatment, which may persuade a patient to undergo a fanciful or unnecessary treatment. A balance should be achieved between the need for disclosing necessary and adequate information and at the same time avoid the possibility of the patient being deterred from agreeing to a

mediLAW necessary treatment or offering to undergo an unnecessary treatment.”

Is the consent given for a diagnostic procedure also valid as consent for therapeutic treatment? The two procedures are different and require a separate consent for each. In the Samira Kohli vs. Dr. Prabha Manchanda and Ors. I (2008) CPJ 56 (SC), the Hon’ble Supreme Court summarized the principles relating to consent as follows: “32. iii: Consent given only for a diagnostic procedure, cannot be considered as consent for therapeutic treatment. Consent given for a specific treatment procedure will not be valid for conducting some other treatment procedure. The fact that the unauthorized additional surgery is beneficial to the patient, or that it would save considerable time and expense to the patient, or would relieve the patient from pain and suffering in future, are not grounds of defence in an action in tort for negligence or assault and battery. The only exception to this rule is where the additional procedure though unauthorized, is necessary in order to save the life or preserve the health of the patient and it would be unreasonable to delay such unauthorized procedure until patient regains consciousness and takes a decision.”

percussion, auscultation and routine sonography (which would include echocardiography). Implied consent is consent assessed when the surrounding circumstances lead a reasonable person to believe that consent has been granted even though word of agreement were not direct, express or explicit.

In an action for negligence/battery for performance of an unauthorized surgical procedure, can the doctor defend himself by stating that consent was given for a particular operative procedure which implied consent for any additional or further operative procedures performed in the interests of the patient? Certain international case laws explain the situation. ÂÂ

The Supreme Court of Canada (Murray v. McMurchy 1949 (2) DLR 442) was considering a claim for battery by a patient who underwent a cesarean section. During the course of cesarean section, the doctor found fibroid tumors in the patient’s uterus. Being of the view that such tumors would be a danger in case of future pregnancy, he performed a sterilization operation. The court granted the claim for damages for battery to the complaining patient. It was held that sterilization could not be justified under the principle of necessity, as there was no immediate threat or danger to the patient’s health or life and it would not have been unreasonable to postpone the operation to secure the patient’s consent. The fact that the doctor found it convenient to perform the sterilization operation without consent as the patient was already under general anesthetic was held to be not a valid defense.

ÂÂ

A somewhat similar view was expressed by Courts in England in Re: F. (supra). It was held that the additional or further treatment which can be given (outside the consented procedure) should be confined to only such treatment as is necessary to meet the emergency, and as such needs to be carried out at once and before the patient is likely to be in a position to make a decision for himself. The court observed: “….Where, for example, a surgeon performs an operation without his consent on a patient temporarily rendered unconscious in an accident, he should do no more than is reasonably required, in the best interests of the patient, before he recovers consciousness. I can see no practical difficulty arising from this requirement, which derives from the fact that the patient is expected before long to regain consciousness and can then be consulted about longer term measures…..”

Can there be a common consent for diagnostic and operative procedures? In the same judgment, Samira Kohli vs. Dr. Prabha Manchanda, the Hon’ble Supreme Court stated: “32. iv. There can be a common consent for diagnostic and therapeutic procedures where they are contemplated. There can also be a common consent for a particular surgical procedure and an additional or further procedure that may become necessary during the course of surgery.”

Is extended consent not implied? No, extended consent is not implied. Implied consent (tacit consent) is the most common variety and is generally accepted in the practice of a family physician or consultant who generally prescribes medicines after noting the history of the patient and physical examination. The fact that a patient comes to a doctor for treatment of an ailment implies that he is agreeable to medical examination in the general sense. This is implied consent and would encompass physical examination (not intimate examination), palpation,

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mediLAW ÂÂ

ÂÂ

The decision of Supreme Court of Canada, in the case referred to above, illustrates the exception to the rule, that an unauthorized procedure may be justified if the patient’s medical condition brooks no delay and warrants immediate action without waiting for the patient to regain consciousness and take a decision for himself. In that case, the doctor discovered a grossly diseased testicle while performing a hernia operation. As the doctor considered it to be gangrenous, posing a threat to patient’s life and health, the doctor removed it without consent, as a part of the hernia operation. An action for battery was brought on the ground that the consent was for a hernia operation and removal of testicle was not consent. The claim was dismissed. The court was of the view that the doctor can act without the consent of the patient where it is necessary to save the life or preserve the health of the patient. Thus, the principle of necessity by which the doctor is permitted to perform further or additional procedure (unauthorized) is restricted to cases where the patient is temporarily incompetent (being unconscious), to permit the procedure delaying of which would be unreasonable because of the imminent danger to the life or health of the patient.

seeing the surgeon, he was given a surgical consent form to sign which gave the surgeon authority to do whatever procedure he thought best. When he saw the surgeon it was agreed that 11 teeth would be pulled. He went to the hospital, signed another general consent, and while he was under general anesthesia, the surgeon pulled 27 teeth. The court upheld his action for battery as to the 16 teeth for which no consent had been obtained.

In case of failure to obtain proper consent a doctor would be exposed to charge of battery (which is a criminal charge), besides being liable for civil action for monetary compensation by way of damages for performing a procedure or investigation without consent of the individual concerned.

During an appendectomy the surgeon discovered that his patient had several large ovarian cysts, which he punctured. The patient sued him for assault and battery but did not allege negligence. The Court dismissed the action and stated that it was “unreasonable to hold a physician to the exact operation that the preliminary examination indicates is necessary. A complete diagnosis may not be possible until the incision is made. The surgeon may extend the operation to remedy any abnormal or diseased condition in the area of the original incision whenever he, in the exercise of sound professional judgment, determines that correct surgical procedure demands it.

A leading case where for want of proper consent the Court held that the action of the doctor amounted to battery and awarded damages in favor of the patient and against the doctor was Bailey vs. Belinfante summarized below: A patient was referred by his dentist to an oral surgeon. While waiting in the waiting room, and before even

Where there is no emergency condition, before the surgeon proceeds to extend surgery he should attempt to get the consent of someone in the patient’s family. If this is not possible, he should probably decide not to extend the scope of the surgery unduly. An extension of a minor operation into a major one is usually considered assault and battery in the absence of an emergency. However, want of consent would not impede a doctor from extending the operation if the said extension was demanded in exercise of sound professional judgment and was required to remedy any abnormal or diseased condition of the patient. The Courts have upheld, in another case (Kennedy vs. Parrott), surgery which was extended beyond the consent taken and observed as under:

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INSPIRATIONAL Story

Blue Hummingbird

nce, long ago, there was a young boy who lived in a distant land called Tandow. He was a cheerful lad with not a care in the world. A special friend had he, the little blue hummingbird. Now this little boy didn’t have a lot of great friends, but the little bird and the boy were inseparable friends. The boy loved the little humming bird, so he built him a home. The bird also loved the boy and would follow him wherever he would go. As time went by their love grew and grew. Then one day the young lad met a pretty young girl in school. The girl had long blonde hair, blue eyes, and a cute little smile. This was about the time of the biggest dance of the year. All the boy could think about was how he would love to take the girl to the dance. He gathered his courage all day and at the end of school confronted the girl and asked her to go with him to the dance. Now this young girl was very popular and felt she did not want to be seen with the boy who cared for her so, but she did not want to hurt his feelings and so figured out a way to avoid saying no or yes. She told the boy if he brought her a red rose she would allow him to escort her to the dance. This hurt the little boy because he knew that in the land of Tandow there had never been a red rose. In fact, the only roses in the land Tandow were white. On the way home the boy kept mumbling to himself why couldn’t she have asked for a white rose. There were hundreds of them in his front yard. Feeling sorry for himself the boy didn’t even notice his friend the hummingbird fluttering above him. Now the bird loved him so, that it could tell instantly the boy was troubled. The bird hovered closer as the boy mumbled on home. Now the bird knew why the boy

was so troubled. The bird could not rest all the night long, it pondered all night, a solution to the boy’s problem. Finally as the sun began to rise the answer to how the bird could help his best friend entered his mind. The little blue hummingbird flew to a rose bush and searched for a large rose with a stem bearing thorns directly above it. Now the bird chose a thorn and with all the power in his wings cast his small body against the sharp thorn. It entered with great pain, as the tear drops of blood fell upon the white petals of the rose. Now as the boy was ready for school, as he left the house he saw a red rose, he could hardly believe it, he ran to the bush and plucked the red rose. In his excitement he failed to notice the lifeless little body that lay below the bush in a puddle of blood. Happy as could be, he began with his red rose on his way to school. Before he got there some other boys playing football in a field called to him and asked him to come and play. His first thought was, no, he had something more important to do. But they begged him and said they really needed him to even the teams. He looked at the rose, then them, then back at the rose. He said to himself. Ah!!! She didn’t really want to go with me anyway. Then, throwing the rose down, the boy went and played football. You’ve probably already figured out the allegory… ÂÂ The boy is each of us. ÂÂ The humming bird is Jesus Christ. ÂÂ The girl is eternal life. ÂÂ The rose is the atonement. ÂÂ The football game is the worldly things we

sometimes feel are so important.

―― “A successful man is one who can lay a firm foundation with the bricks others have thrown at him.” ―David Brinkley “True dignity is never gained by place, and never lost when honors are withdrawn.” ―Philip Massinger “Friendship consists in forgetting what one gives and remembering what one receives.” ―Alexander Dumas

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lighter reading

The wife put down her drink and said, “Let the old man dig. I had him buried upside down.”

Overloaded My wife, a flight attendant for a major airline, watched one day as a passenger overloaded with bags tried to stuff his belongings in the overhead bin of the plane. Finally, she informed him that he would have to check the oversized luggage.

The Anesthesiologist Jill received a bill from the hospital for her recent surgery, and was astonished to see a $900 fee for the anesthesiologist. She called his office to demand an explanation.

“When I fly other airlines,” he said irritably, “I don’t have this problem.”

“Is this some kind of mistake?” Jill asked when she got the doctor on the phone. “No, not at all,” the doctor said calmly.

My wife smiled, “When you fly other airlines, I don’t have this problem either.” Threatening Letters

“Well,” said Jill, “that’s awfully costly for knocking someone out.”

The fellow stormed into the postmaster’s office in a fury. “I’ve been getting threatening letters in the mail for months and I want them stopped.”

“Not at all,” replied the doctor. “I knock you out for free. The 900 dollars is for bringing you back around.”

“Of course,” said the postmaster. “Sending threatening letters through the mail is a federal offence. Do you know who’s sending them?” “Yes,” shouted the man. “It’s those idiots down at the Internal Revenue Service.” An Old Woman An old man and woman were married for years, even though they hated each other. When they had a confrontation, screaming and yelling could be heard deep into the night. The old man would shout, “When I die, I will dig my way up and out of the grave and come back and haunt you for the rest of your life!”

Quote

“The secret of a good sermon is to have a good beginning and a good ending; and to have the two as close together as possible.” —George Burns

Dr. Good and Dr. Bad Situation: A patient came with tubercular pericarditis.

No steroids are needed

Start steroids

Neighbors feared him because of the many strange occurrences that took place in their neighborhood. The old man liked the fact he was feared. To everyone’s relief, he died of a heart attack when he was 68. His wife had a closed casket at the wake. After the burial, she went straight home and began to party as if there was no tomorrow. Her neighbors, concerned for her safety, asked, “Aren’t you afraid that he may indeed be able to dig his way up and out of the grave and come back and haunt you for the rest of your life?”

©IJCP Academy

LAUGH-A-WHILE

Lighter Side of Medicine

Lesson: The current recommendation is to use corticosteroids for patients with constrictive tuberculous pericarditis and for those felt to be at high risk of developing the condition (i.e., large effusion, high level of pericardial fluid inflammatory cells, or early signs of constriction). KK Aggarwal

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Information for Authors Manuscripts should be prepared in accordance with the ‘Uniform requirements for manuscripts submitted to biomedical journals’ compiled by the International Committee of Medical Journal Editors (Ann. Intern. Med. 1992;96: 766-767). Indian Journal of Clinical Practice strongly disapproves of the submission of the same articles simultaneously to different journals for consideration as well as duplicate publication and will decline to accept fresh manuscripts submitted by authors who have done so. The boxed checklist will help authors in preparing their manuscript according to our requirements. Improperly prepared manuscripts may be returned to the author without review. The checklist should accompany each manuscript. Authors may provide on the checklist, the names and addresses of experts from Asia and from other parts of the World who, in the authors’ opinion, are best qualified to review the paper. Covering letter –

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Note: Please keep a copy of your manuscript as we are not responsible for its loss in the mail. Manuscripts will not be returned to authors. Title page Should contain the title, short title, names of all the authors (without degrees or diplomas), names and full location of the departments and institutions where the work was performed,

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name of the corresponding authors, acknowledgment of financial support and abbreviations used. – The title should be of no more than 80 characters and should represent the major theme of the manuscript. A subtitle can be added if necessary. – A short title of not more than 50 characters (including inter-word spaces) for use as a running head should be included. – The name, telephone and fax numbers, e-mail and postal addresses of the author to whom communications are to be sent should be typed in the lower right corner of the title page. – A list of abbreviations used in the paper should be included. In general, the use of abbreviations is discouraged unless they are essential for improving the readability of the text. Summary – The summary of not more than 200 words. It must convey the essential features of the paper. – It should not contain abbreviations, footnotes or references. Introduction – The introduction should state why the study was carried out and what were its specific aims/objectives. Methods – These should be described in sufficient detail to permit evaluation and duplication of the work by others. – Ethical guidelines followed by the investigations should be described. Statistics The following information should be given: – The statistical universe i.e., the population from which the sample for the study is selected. – Method of selecting the sample (cases, subjects, etc. from the statistical universe). – Method of allocating the subjects into different groups. – Statistical methods used for presentation and analysis of data i.e., in terms of mean and standard deviation values or percentages and statistical tests such as Student’s ‘t’ test, Chi-square test and analysis of variance or non-parametric tests and multivariate techniques. –

Confidence intervals for the measurements should be provided wherever appropriate.

Results – These should be concise and include only the tables and figures necessary to enhance the understanding of the text.

Discussion –

This should consist of a review of the literature and relate the major findings of the article to other publications on the subject. The particular relevance of the results to healthcare in India should be stressed, e.g., practicality and cost.

References These should conform to the Vancouver style. References should be numbered in the order in which they appear in the texts and these numbers should be inserted above the lines on each occasion the author is cited (Sinha12 confirmed other reports13,14...). References cited only in tables or in legends to figures should be numbered in the text of the particular table or illustration. Include among the references papers accepted but not yet published; designate the journal and add ‘in press’ (in parentheses). Information from manuscripts submitted but not yet accepted should be cited in the text as ‘unpublished observations’ (in parentheses). At the end of the article the full list of references should include the names of all authors if there are fewer than seven or if there are more, the first six followed by et al., the full title of the journal article or book chapters; the title of journals abbreviated according to the style of the Index Medicus and the first and final page numbers of the article or chapter. The authors should check that the references are accurate. If they are not this may result in the rejection of an otherwise adequate contribution. Examples of common forms of references are: Articles Paintal AS. Impulses in vagal afferent fibres from specific pulmonary deflation receptors. The response of those receptors to phenylguanide, potato S-hydroxytryptamine and their role in respiratory and cardiovascular reflexes. Q. J. Expt. Physiol. 1955;40:89-111.

Figures – Two complete sets of glossy prints of high quality should be submitted. The labelling must be clear and neat. – All photomicrographs should indicate the magnification of the print. – Special features should be indicated by arrows or letters which contrast with the background. – The back of each illustration should bear the first author’s last name, figure number and an arrow indicating the top. This should be written lightly in pencil only. Please do not use a hard pencil, ball point or felt pen. – Color illustrations will be accepted if they make a contribution to the understanding of the article. –

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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.

6. Suggestions for reviewers (name and postal address)

Articles in Books

2.____________ 2.________________

Strong MS. Recurrent respiratory papillomatosis. In: Scott Brown’s Otolaryngology. Paediatric Otolaryngology Evans JNG (Ed.), Butterworths, London 1987;6:466-470.

3.____________ 3.________________

4.____________ 4.________________

Tables –

These should be typed double spaced on separate sheets with the table number (in Roman Arabic numerals) and title above the table and explanatory notes below the table.

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Online Submission Also e-Issue @ www.ijcpgroup.com For Editorial Correspondence

Dr KK Aggarwal

Group Editor-in-Chief Indian Journal of Clinical Practice E-219, Greater Kailash, Part-1 New Delhi - 110 048. Tel: 40587513 E-mail: editorial@ijcp.com Website: www.ijcpgroup.com

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POSTAL REGISTRATION NO. DL (S)-01/3200/2012-2014 Posted in N.D. PSO New Delhi