JAMS-Surgery by IJCP

Journal of Applied

MEDICINE & SURGERY Volume 1, Issue 2, January-March 2012

Journal of Applied MEDICINE & SURGERY

Volume 1, Issue 2 January-March 2012

JAMS Editorial Panel Editor-in-Chief SM Rajendran Executive Editor Jayakar Thomas

Associate Editor S Bhuminathan

JAMS Advisory Board Radiology Chandrasekar V

Anatomy Johnson WMS

Biochemistry Shanthi B

Microbiology Chitralekha S

Dentisry Masthan KMK

Orthopaedics Sivakumar A

Pharmacology Inbaraj SD

Pathology Monika G

Community Medicine Steven T

Nephrology Jayakumar M

Surgery Ravishankar S

Forensic Medicine Tahera Begum

Anatomy Jayanthi V

Physiology Saikumar P

IJCPâ&#x20AC;&#x2122;s Editorial Panel Dr Sanjiv Chopra Prof. of Medicine & Faculty Dean Harvard Medical School Group Consultant Editor

Dr Deepak Chopra Chief Editorial Advisor

Dr KK Aggarwal CMD, Publisher and Group Editor-in-Chief Dr Veena Aggarwal MD & Group Executive Editor

Anand Gopal Bhatnagar Editorial Anchor

Advisory Bodies Heart Care Foundation of India, Non-Resident Indians Chamber of Commerce & Industry, World Fellowship of Religions

Contents From the desk of editor-in-chief

From the desk of executive editor

From the Desk of IJCP Group Editor-in-Chief

review article New Rapid Bedside Test to Predict Preterm Delivery: phIGFBP-1 in Cervical Secretions

Hypertension Challenges in Diabetics

Headache â&#x20AC;&#x201C; A Review

Postprandial Hyperglycemia, Implications and Control

Anemia of Chronic Disease and Periodontitis: The Missing Link

Aspirin Resistance

clinical study Clinical Outcome in Malaria - Reiterating the Role of Parasitic Index

case report Epidermal Nevus Syndrome with Hemihypertrophy of the Body

Fibrothecoma of Ovary with Torsion: A Rare Case of Ovarian Tumor

Idiopathic Sclerosing Encapsulating Peritonitis Presenting As Spontaneous Multiple Jejunocolic Fistula

Bilateral Ovarian Fibromatosis with Ascites

An Unusual Case of Hepatitis E Induced Fulminant Hepatic Failure

Oocyte Donation: Pregnancy Results and Obstetric Outcome

Seasonal Influenza: Clinical Crossroads in Diagnosis and Management

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From the desk of editor-in-chief

Prof. SM Rajendran

M.D., F.R.C.P., (Glasgow), F.I.M.S.A. Registrar, Bharath University, Chennai Former Prof. & Head, Dept. of Medicine and Diabetology Stanley Medical College and Hospital, Chennai

Dear Readers I Hope the First Issue which was circulated, has given sufficient informationâ&#x20AC;&#x2122;s, and you would have appreciate the Journal brought out by Sri Balaji Medical College and Hospital, Bharath University, Chennai. Still we are at cradle stage only. We will try to quench your thirst in the Forth coming Issues. Really I am very happy about the encouragement which was showered over us. We request your kind patron and continued encouragement for this Journal by providing your valuable ideas and also we will be happy if you could send your articles etc. My heartiest thanks to our patronâ&#x20AC;&#x2122;s Dr. J. Sri Nisha, M.D.S., who has extended all her support. Our Executive Editor Prof. Jayakar Thomas who is doing commendable jobs to satisfy all type of clinicians, Soon It will be very unique one I wish all our readers have a happy reading. n

Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

From the desk of executive editor

Prof. Jayakar Thomas

Executive Editor MD., DD., MNAMS., PhD., FAAD, FRCP (Edin) FRCP (Glasgow), FRCP (London)

Dear Readers, At the outset I thank you all for the overwhelming support that you had given for the first issue of JAMS. That surely was a fillip to our enthusiasm as we moved forward to this second issue. We did receive a lot of suggestions to improvise and we did sincerely attempt to take them and compose this issue with a reasonable mix of case reports, reviews, and commentaries. In my role as the Executive Editor, I have put in some extra efforts towards making this issue more readerfriendly. I must quickly add that we are still in the infant stage and look forward to more constructive ideas to make JAMS more reading-worthy. Our Chief Editor Prof. S. M. Rajendran has been by my side to help me from all angles and for this I salute him. My grateful thanks goes to our patron Dr. J. Srinisha for all her support. It is about â&#x20AC;&#x2DC;Making the Differenceâ&#x20AC;&#x2122;! It is indeed a time to celebrate! I wish all of you happy reading. n

Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

From the Desk of IJCP Group Editor-in-Chief

Dr KK Aggarwal

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

OPD Management Of Acute Pulmonary Embolism Not all symptomatic patients with acute pulmonary embolism need to be admitted to the hospital for initial therapy. Patients with symptomatic acute PE and a low risk of death (PE severity index- PESI- low risk) can be treated as an OPD case with subcutaneous low molecular weight heparin followed by oral anticoagulation. Prognostic models The simplified PESI assigns a point for each of the following variables  Age >80 years  A history of cancer  Chronic cardiopulmonary disease  Heart rate ≥110 beats per minute  Systolic blood pressure <100 mmHg  Arterial oxyhemoglobin saturation <90 percent. A total point score of zero indicates a low risk for mortality, while a score of one or more indicates a high risk. n

Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

review article

New Rapid Bedside Test to Predict Preterm Delivery: phIGFBP-1 in Cervical Secretions Urmila Karya*, Neera Singh**, Priyanka Garg†, Shakun Singh‡

Abstract Objective: Phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1) is secreted by decidual cells and leaks into cervical secretions when fetal membranes detach from decidua. Our aim was to assess whether detection of cervical phIGFBP-1 by a rapid bedside test could be used to diagnose preterm labor. Material and methods: In our prospective study, 80 pregnant females between 28-36 weeks of gestation with regular persistent uterine contractions >10/hour (Study group) and 80 females of similar gestation without symptoms of preterm labor (Control group), were assessed for the presence of cervical phIGFBP-1 by a one step dipstick test (Actim Partus test). Tocolysis and steroid therapy were administered in all cases of study group. All patients were followed till delivery. Results: Preterm birth rate was significantly higher in Actim Partus test-positive patients. The admission to delivery interval was significantly shorter (mean: 2.3 days) in test-positives as compared to 5.1 days in test-negative group. Conclusion: Actim Partus test is a rapid and easily applicable test which highly anticipates preterm delivery in patients at risk. An ultrasonographic cervical length measurement obtained from patients with uterine contractions at 28-35 weeks gestation may avoid overdiagnosis. Key words: PhIGFBP-1, Actim Partus test, preterm labor

reterm labor, defined as regular uterine contractions accompanied by effacement and dilatation of cervix after 20 weeks and before 37 completed weeks of gestation continues to be the most common problem in obstetrics today and a major financial burden on healthcare system. Unfortunately, many women who experience preterm labor and delivery do not have recognizable risk factors. Overall sensitivity of risk scoring systems to identify patients at risk of preterm labor is less than 50% as reported by the American College of Obstetricians and Gynecologists (ACOG). Besides no single test is able to predict preterm labor confidently. Insulin-like growth factor binding protein-1 (IGFBP-1) belongs to the super family of insulin-like binding proteins. Out of six subtypes, a highly phosphorylated from (phIGFBP-1) is found in the decidual tissues. Amniotic fluid contains nonphosphorylated and lesser phosphorylated isoforms. Because of this difference in the origin of IGFBP-1, decidual or amniotic fluid can be identified through the use of monoclonal *Associate Professor **Junior Resident † Lecturer ‡ Assistant Professor Dept. of Obstetrics and Gynecology LLRM Medical College, Meerut

Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

antibodies. The process of labor is hypothesized to disrupt the choriodecidual interface, releasing phIGFBP-1 in the cervical secretions. Developments in biomedical engineering have allowed the development of commercial bedside test kit for the qualitative detection of phIGFBP-1 above the level of 10 µg/l. In this prospective study, we have tried to evaluate the efficacy of bedside test kit for phIGFBP-1 detection in predicting preterm delivery. Material and Methods The present study was conducted in the Dept. of Obstetrics and Gynecology, SVBP Hospital associated to LLRM Medical College, Meerut for a period of one and a half year from September 2008 to February 2010. Study Design

A prospective cohort study. Study included pregnant females between 28-36 weeks gestation selected from indoor wards and obstetrics OPD. Subjects were divided into two groups. Study group: Eighty pregnant females with regular persistent uterine contractions (>10/hour). Control group: Eighty pregnant females without symptoms of preterm labor.

Review Article Inclusion criteria for study group  Gestational age between 28-36 weeks  Regular uterine contractions: Three or more in 10 minutes  Cervical dilatation >1 cm; <3 cm  Intact membranes Exclusion criteria in both groups  Pregnancies complicated by any other maternal or fetal condition n Multiple pregnancies n Polyhydramnios n Diabetes n Heart disease n Ruptured membrane n Antepartum hemorrhage Detailed history of all patients was taken regarding name, age, parity, socioeconomic status, occupation, nutritional status, period of gestation, past history of and family history of hypertension, diabetes mellitus, renal disease. Gestational age was calculated based on the last menstrual period and confirmed by first or early second trimester ultrasonography when discrepancy of more than 10 days occurred, gestational age was set only by first trimester ultrasonographic examination. A detailed general, systemic and obstetric examination was done. Data collection included demographic variables (age, parity, gravidity, previous preterm delivery). Before digital cervical examination, a Table 1. Distribution of Patients on Basis of Predisposing Factors in Study Group Factors

Study group No.

Low socioeconomic status

UTI

7.5

Previous abortions

12.5

Previous preterm delivery

12.5

Previous LSCS

7.5

Inadequate check-up

Heavy work

Smoking

Small stature

Poor nutrition

speculum examination was performed. Dry dacron swab was placed in the cervix at external os for 10-15 seconds then the swab was removed, washed in the test reagent for 20-40 seconds and analyzed using the bedside PhIGFBP-1 test kit after five minutes. Results were reported either as positive or negative. In all patients, digital examination was done for cervical dilatation and effacement. Investigations like hemoglobin, blood-group ABo/Rh, hemogram in study group, HIV counseling and testing, VDRL, HBsAg, urine R/M examination, blood sugar, cervical swab culture, Actim Partus test, ultrasonography for fetal well-being, period of gestation, AFI, placenta localization, congenital malformation were done. The managing obstetrician was blinded to the result of test and clinical care was administered according to hospital’s clinical guidelines for the management of preterm labor by tocolysis with oral nifedipine and corticosteroid therapy. Following delivery, data regarding gestational age at delivery, admission to delivery interval, and baby status was compiled. The results were analyzed using appropriate statistics and were presented as mean ± SD as percentage of baseline for comparing data in different groups at various levels. p < 0.05 was considered statistically significant and p < 0.001 was considered highly significant. Results and Discussion Study and control groups were similar in sociodemographic profile (age, parity, socioeconomic status, etc.) (Table 1). As shown in observation Table 2, the Actim Partus test was positive in 26 and 12 subjects in study and control group, respectively and negative in 54 and 68 subjects, respectively. Comparing the results of Tables 2, 4 and 5; the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of phIGFBP-1 test for preterm delivery was 70%, 91.66%, 73.66%, 90.16%, respectively. The high NPV may be of great value in avoiding unnecessary interventions with potentially hazardous medications in patients with uterine contractions. The chorion-decidua complex produces many proteins including fetal fibronectin (FFN), interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor-α. All of these Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

Review Article Table 2. Actim Partus Test Results Test

Study group

Control group

No.

Positive

32.50

Negative

67.50

Total

100

c2 = 2.088 (df = 1); p = 0.148; OR = 2.73; 95% CI: -0.39-2.40

Table 3. Distribution of Patients according to Period of Gestation in Study and Control Groups Period of gestation

Study group

Control group

95% CI

No.

Lower

Upper

28-30

7.50

0.01

-5.95

-2.55

30-32

7.36

0.41

3.58

32-34

8.14

-0.02

4.22

34-36

17.50

–

Total

100

c2 = 36.271; p < 0.001

Table 4. Admission to Delivery Interval as compared to Test Results Test phIgfbp-1

Positive

Negative

No.

78.94

9.84

>7 days

21.06

110

90.16

Total

100

122

100

0-48 hours

3.00

95% CI Lower

Upper

-0.53

2.73

c2 = 20.193 (df = 1); p < 0.001

proteins have been evaluated as biochemical markers of threatened preterm delivery. The most extensively used is FFN. However, the sensitivity, specificity and predictive values of cervical FFN is not superior to phIGFBP-1 test in most of the studies. One possible advantage is that only minimal amounts of phIGFBP-1 are present in urine and seminal plasma. Hence, recent intercourse and urinary contamination of the sample do not affect the test results.

Table 5. Comparison of Test Results with Gestational Age at Delivery and Admission-to-delivery Interval

As shown in Table 3, the performance of phIGFBP-1 was significantly better when levels were tested at 30 weeks (AUC for test performed at 28 weeks: 0.50 (range, 0.32-0.69) at 30 weeks: 0.79 (range 0.68-0.89) and at 34 weeks: 0.65 (range 0.48-0.83). A positive test result at 30 weeks had a detection rate for delivery at <34 weeks and <37 weeks of 83.3% and 56%, respectively. Kekki et al showed that women with a phIGFBP-1 concentration of at least 10 µg in a cervical

Test-positive (n = 12)

33 ± 0.6

3.3 ± 0.8

Test-negative (n = 68)

35 ± 0.8

5.1 ± 1.4

Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

Gestational age (in weeks)

Admission-todelivery interval

Test-positive (n = 26)

32 ± 0.8

2.3 ± 1.2

Test-negative (n = 54)

35 ± 0.5

5.1 ± 1.4

Study group

p value

<0.001

Control group

p value

0.002

swab sample had a 10-fold risk of preterm delivery compared with women in whom the concentrations of phIGFBP-1 concentration was <10 µg. In our study, we used a bedside fast-reacting test kit (Actim Partus

Review Article Table 6. Birth Weight at the Time of Delivery in both Groups Birth weight (kg)

Study group No.

Control group %

No.

95% CI Lower

Upper

≤1.5

2.5

0.23

—3.93

1.00

1.5 -2.0

45.0

7.36

0.41

3.58

2.0 -2.5

47.5

0.30

—2.39

-0.01

1.00

—2.46

2.46

≥2.5

5.0

Total

100

c2 = 8.179; p = 0.042.

kit), which yielded qualitative results with a similar sensitivity of 10 µg. Lembet et al carried out a prospective study on 36 women between 20 and 36 weeks of gestation with regular contractions. The sensitivity, specificity, PPV and NPV of the rapid phIGFBP-1 test for preterm delivery were 89.5%, 94.1%, 94.4% and 88.9%, respectively. Our current results show a test with a very reasonable accuracy and which is easy to use. The women who tested negative for IGFBP-1 experienced a reduced need for hospitalization and tocolysis, as well as substantial prolongation in pregnancy, compared to the women who tested positive. These date suggest that this bedside test has a role in the diagnosis or exclusion of premature labor and delivery in symptomatic women. Also the risk of preterm delivery increases substantially when positive results occur in the presence of cervical secretions changes. As all of the women in our study received tocolysis, there is a possibility that the test serves to identify women less likely to respond to tocolysis. The next step would be to assess the effect of with holding tocolytic therapy in women who tested negative. Conclusion The bedside fast reacting test for phIGFBP-1 shows promising results in the diagnosis and exclusion of premature labor and delivery in symptomatic women. If larger studies confirm our initial results, the test may replace cervical ultrasound, FFN test in the future or at least serve as a useful adjunct to these tests. Fallacies: High cost of the test; a weakly positive test report. 10

Suggested Reading 1. Altinkaya O, Gungor T, Ozat M, Danisman N, Mollamahutgulo L. Cervical phosphorylated insulin-like growth factor binding protein-1 in prediction of preterm delivery. Arch Gynecol Obstet 2002;279(3):279-83. 2. Balii D, Latifagic A, Hudii I. Insulin-like growth factorbinding protein-1 (IGFBP-1) in cervical secretions as a predictor of preterm delivery. J Matern Fetal Neonatal Med 2008;21(5):297-300. 3. Ballard PL, Ballard RA. Scientific basis and therapeutic regimens for use of antenatal glucocorticoid. Am J Obstet Gynecol 1995;173(1):254-62. 4. Bittar RE. Cervical insulin-like growth factor-binding protein-l (phIGFBP-1) in patients at increased risk for preterm delivery: preliminary results. In: The bBook of Abstracts of 5th World Congress of Perinatal Medicine, Istanbul, Turkey, 1999. Abstract MS2-1, p.45. The International Society of Perinatal Medicine, Barceloma, Spain. 5. Bittar RE, da Fonseca EB, de Carvalho MH, Martinelli S, Zugaib M. Predicting preterm delivery in asymptomatic patients with prior preterm delivery by measurement of cervical length and phosphorylated insulin-like growth factor-binding protein-1. Ultrasound Obstet Gynecol 2007;29(5):562-7. 6. da Fonseca EB, Bittar RE, Carvalho MH, Zugaib M. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study. Am J Obstet Gynecol 2003;188(2):419-24. 7. Das B, Gogoi MD. A clinical study of preterm labour. J Obstet Gynaecol India 1986;34:300. 8. Elizur SE, Yinon Y, Epstein GS, Seidman DS, Schiff E, Sivan E. Insulin-like growth factor binding protein-1 detection in preterm labor: evaluation of a bedside test. Am J Perinatol 2005;22(6):305-9. 9. Eroglu D, Yanik F, Oktem M, Zeyneloglu HB, Kuscu E. Prediction of preterm delivery among women Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

Review Article with threatened preterm labor. Gynecol Obstet Invest 2007;64(2):109-16. 10. Frost RA, Tseng L. Insulin-like growth factor-binding protein-1 is phosphorylated by cultured human endometrial stromal cells and multiple protein kinases in vitro. J Biol Chem 1991;266(27):18082-8. 11. Gomez R, Galasso M, Romero R, Mazor M, Sorokin Y, Gonçalves L, et al. Ultrasonic examination of the uterine cervix is better than cervical digital examination as a predictor of the likelihood of premature delivery in patients with preterm labor and intact membranes. Am J Obstet Gynecol 1994;171(4):956-64. 12. Halle M. Assessment of risk of premature birth using phosphorylated IGFBP-1 as a rapid test in comparison with fibronectin determination. In: The Book of Abstracts of Congress of Deutshe Gesellsehaft for Perinatal und Geburts-medizin. Berlin, Germany, 1999. Abstract ICRI 07-2-76, P.254. International Society Immunology of Reproduction, Chicago, II, USA. 13. Julkunen M, Koistinen R, Aalto-Setälä M, Janne OA, Kontula K. Primary structure of human insulin-like growth factor-binding protein/placental protein 12 and tissue-specific expression of its mRNA. FEBS Lett 1988;236(2): 295-302. 14. Kekki M, Kurki T, Paavonen J, Rutanen EM. Insulinlike growth factor binding protein-1 in cervix as a marker of infectious complications in pregnant women with bacterial vaginosis. Lancet 1999;353:1494. 15. Kekki M, Kurki T, Kärkkäinen, Hiilesmaa V, Paavonen J, Rutanen EM. Insulin-like growth-factor binding

protein-1 in cervical secretion as a predictor of preterm delivery. Acta Obstet Gynecol Scand 2001;80(6): 546-51. 16. Lembet A, Eroglu D, Ergin T, Kuscu E, Zeyneloglu H, Batioglu S, et al. New rapid bed-side test to predict preterm delivery: phosphorylated insulin-like growth factor binding protein-1 in cervical secretions. Acta Obstet Gynecol Scand 2002;81(8):706-12. 17. Akercan F, Kazandi M, Sendag F, Cirpan T, Mgoyi L, Terek MC, et al. Value of cervical phosphorylated insulinlike growth factor binding protein-1 in the prediction of preterm labor. J Reprod Med 2004;49(5):368-72. 18. Nuutila M, Hiilesmaa V, Kärkkäinen T, Ylikorkala O, Rutanen EM. Phosphorylated isoforms of insulin-like growth factor binding protein-1 in the cervix as a predictor of cervical ripeness. Obstet Gynecol 1999;94(2):243-9. 19. Rutanen EM, Pekonen F, Kärkkäinen T. Measurement of insulin-like growth factor binding protein-1 in cervical/ vaginal secretions: comparison with the ROM-check membrane immunoassay in the diagnosis of ruptured fetal membranes. Clin Chim Acta 1993;214(1):73-81. 20. Shine BK, Kim SJ, Park WI, Kim JO, Kim DN, Hong SY, et al. Insulin-like growth factor-binding protein-1 in cervical secretion as a predictor of preterm delivery. Korean J Obstet Gynecol 2001;44(2):2250-6. 21. Tanir HM, Sener T, Yildiz Z. Cervical phosphorylated insulin-like growth factor binding protein-1 for the prediction of preterm delivery in symptomatic cases with intact membranes. J Obstet Gynaecol Res 2009;35(1):66-72.

Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

review article

Hypertension Challenges in Diabetics AR Vijayakumar*, T Geetha**, KB Rojith†

Abstract Hypertension (HT) is one of the important risk factor for cardiovascular morbidity and mortality in diabetic patients. Tight control of HT which always needs two or more antihypertensives along with tight glycemic control can prevent or retard microvascular and macrovascular complications associated with diabetes. ACE inhibitors and ARBs remain the first choice of antihypertensives in diabetes and the role of lifestyle modifications, statins and aspirin also need to be emphasized. Key words: Diabetes, hypertension, ACE inhibitors, ARBs, diabetic nephropathy

atients with diabetes mellitus (DM) have a much higher rate of co-existing hypertension (HT) than would be expected in the general population. HT is one of the modifiable risk factors for developing cardiovascular death. Diabetes increases the risk of coronary events two fold in men and four fold in women. Patients with both diabetes and HT have twice the risk of cardiovascular disease (CVD) as nondiabetic patients with HT alone. About 40% patients with type 1 and 70% of patients with type 2 diabetes with normoalbuminuria have blood pressure (BP) levels of 140/90 mmHg.1 Obesity, ethnicity and age are factors that can affect the development of HT in diabetes. Higher prevalence of HT in diabetes exists among Indians.2 The possibility of dying from cardiovascular complications in hypertensive diabetics is also much higher among Indians.3 Types of HT in diabetic patients and prevalence.4  Essential HT  Hypertension consequent to nephropathy  Isolated systolic HT  Supine HT with orthostatic fall Supine, sitting and standing BP should be measured in all diabetic patients during each visit. *Professor and Former Head **Assistant Professor † Junior Resident Dept. of Medicine, Coimbatore Medical College, Coimbatore Address for correspondence Dr AR Vijayakumar No. 2A, 4th Street, SN DAS Layout Tatabad, Coimbatore - 641 012 E-mail: vatcbe@vsnl.net

In type 1 diabetes: Incidence of HT rises from 5% at 10 years to 33% at 20 years and 70% at 40 years of diabetic history. The rise of BP is closely related to the onset of microalbuminuria and increases progressively as the renal disease progresses. In type 2 diabetes: 40-50% of patients are already hypertensive during the time of diagnosis of DM. In those with HT, approximately 50% had HT even before the onset of microalbuminuria. ADA Recommendations for the Screening of Hypertension in Diabetics  BP should be measured at every routine visit.  Patients found to have a systolic BP of >130 mmHg or a diastolic BP of >80 mmHg should have BP confirmed on separate days.  Repeat systolic BP of >130 mmHg or diastolic BP of >80 mmHg confirms the diagnosis of HT.  The current goal for BP management in patients with diabetes is systolic <130 mmHg and diastolic <80 mmHg. Goals of Therapy The Sixth Report of Joint National Committee (JNC-VI) on prevention, detection, evaluation and treatment of high BP, regards diabetes as a vascular disease equivalent in the management of HT.5 Regardless of the antihypertensive therapy used, a reduction in BP helps to prevent diabetic complications. The appropriate level of BP at which antihypertensive therapy should be started, as well as the current goal of such therapy6 and the best choices of antihypertensive drugs are the major areas of confusion. A target Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

Review Article BP goal of 130/80 mmHg is recommended, if it can be safely achieved. BP lower than 125/75 mmHg is recommended for people who have proteinuria more than 1 g/day and renal insufficiency, regardless of etiology. Moreover UKPDS and HOT studies demonstrated that achievement of lower BP is virtually impossible to achieve with monotherapy. The burden of multidrug therapy can be reduced by extensive attention to lifestyle modifications, which include weight reduction, physical activity and moderation of sodium, protein and alcohol intake. This may improve control over hyperglycemia and dyslipidemia. Steps in the Management of Diabetic Hypertension Correction of Hyperglycemia

A diabetic hypertensive needs to be on diet control along with oral hypoglycemic agents or insulin, depending on the type of diabetes.  In type 1 DM with HT: Insulin therapy is mandatory. Thiozolidinediones increase insulin sensitivity and hence may be used in the above category of patients only if left ventricle (LV) function is normal.7  In type 2 DM with HT with mild renal failure: Sulfonylureas like gliclazide and glimepiride or nonsulfonylurea meglitinide groups of drugs like repaglinide or nateglinide can be used since these are all mainly metabolized in the liver.8 Thiozolidinediones induce fluid retention and hence should not be used in severe HT and hypertensive heart failure. Treatment of Hypertension

A diabetic patient presenting with high normal BP (systolic 120-139 mmHg and diastolic 80-89 mmHg) needs to be evaluated for CVD and other diabetes related complications. Lab tests namely serum creatinine, electrolytes, lipid profile and quantification of urine albumin excretion are required. If no risk factors exist, such patient should be immediately started on lifestyle modifications. If risk factors exist with high normal BP antihypertensive treatment should be started with lifestyle modifications. All hypertensive diabetics with BP >160/100 mmHg irrespective of cardiovascular risk factors, confirmed on Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

two occasions, two weeks apart, should receive liestyle modifications and antihypertensive therapy right at the start itself. Drugs used in the treatment of HT 

   

Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) single/combined Diuretics b-blockers a-blockers Calcium channel blockers (CCB)

Considerations in the Selection of Antihypertensive Treatment Associated co-morbid conditions like coronary artery disease (CAD), congestive cardiac failure (CCF), nephropathy and peripheral vascular disease (PVD) have a role in determining the antihypertensive treatment. If systolic BP is 20 mmHg greater than the goal or if diastolic BP is 10 mmHg above the goal, it is preferable to start therapy with two agents. ACEIs/ARBs are the first-line of drugs due to their renoprotective effect. ACEIs

Maximum experience with ACEIs comes from HOPE study. This trial demonstrated that ACEIs reduce HT in diabetes improves the survival of patients with heart failure, asymptomatic LV dysfunction and myocardial infarction and also reduce the rate of fall in renal function with nephropathy.9,10 ARBs

ARBs have many properties similar to that of ACEIs. Cough is not a problem with their usage, as with ACEIs, since they do not prevent breakdown of bradykinin and other kinins.9 Combination of ACEIs with ARBs reduce the preload and after load in patients with subclinical or overt hypertensive heart failure. This combination uses both the drugs at a low effective dose, so chances of dry cough are much reduced.10 This combination is very useful if there is no reduction of albuminuria in associated diabetic nephropathy or if the BP target levels are not reached. 13

Review Article ACEIs or ARBs may be used in combination with diuretics, b-blockers or CCBs depending on co-morbid conditions. In diabetics with isolated systolic HT, diuretics are of greater benefit. Systolic BP is a stronger predictor of risk than diastolic BP, since it predisposes to CVD and renal dysfunction. Sixty-five percent of diabetic hypertensives have isolated systolic HT, which is also more difficult to control.

and Scottish Inter Collegiate Guidelines. Statins lower BP and correct dyslipidemia accompanying DM.

Diabetic hypertensives with heart failure may be given ACE inhibitors with low doses of thiazide diuretics (12.5-25 mg). Loop diuretics may be used instead of thiazide diuretics in patients with glomerular filtration rate (GFR) - 30 ml/min, corresponding to a serum creatinine of 2.5-3 mg/dl.

Intensive BP control dramatically reduces risk of cardiovascular deaths and microvascular events in diabetic nephropathy. BP target for these patients are lower <130/80 mmHg, than those for diabetes without nephropathy. HOT study has shown that a reduction of diastolic BP from 85-89 mmHg results in a 50% reduction in cardiovascular events in diabetic patients but not in nondiabetic patients. Three to four antihypertensives are usually needed to reach a BP goal of 130/80 mmHg in diabetic patients in general and 125/75 mmHg in patients with proteinuria of 1 g/24 hours with increased serum creatinine. The low-density lipoprotein (LDL) goal in diabetic nephropathy patient is <100 mg/dl and <70 mg/dl in the presence of CVD.

b-blockers can be used in patients with ischemic heart disease (both angina and postmyocardial infarction). Carvedilol is a metabolically neutral compound which reduces myocardial ischemia, has arteriolar vasodilating actions and is an adjunct to diuretics, ACEIs and digoxin in the treatment of heart failure in diabetic subjects. In GEMINI trial, carvedilol added to ACEIs/ARBs has led to improved BP control and reduced microalbuminuria. In diabetic hypertensives with heart failure or with Prinzmetal angina, dihydropyridine (DHP), CCBs may be used. CCBs are not to be used in case of recent coronary event. a-blockers increases insulin sensitivity, improve highdensity lipoprotein (HDL) levels, reduce cholesterol and are beneficial for diabetic hypertensives with benign prostatic hypertrophy in reducing urinary symptoms. Role of Aspirin

ALLHAT, HOT study and Thrombosis Prevention Study have shown that 75 mg aspirin o.d., reduces major cardiovascular incidents by 15% but has as effect as not fatal events. They are indicated in such patients upto 75 years of age, if serum cholesterol >190 mg/dl and 10-year coronary artery risk is >15%.12 It is also indicated in patients with target organ damage or clinical CVD. Role of Statins

Statins lower the risk of stroke and all cause mortality and are safe, simple and well-tolerated as suggested by Joint British Recommendation on prevention of CAD 14

Special Considerations in Diabetic Nephropathy Basic to prevention of diabetic nephropathy is the treatment of its known risk factors, HT, hyperglycemia, smoking and dyslipidemia.

Conclusions  Patients with DM have a much higher rate of HT than would be expected in the general population.  Co-existence of DM and HT increases the risk of macro- and microvascular complications.  BP should be measured in supine, sitting and standing posture in a diabetic patient to detect existence of autonomic neuropathy and drug induced postural hypotension.  Tight BP control (target level 130/80 or below) prevents or retards the progress of both micro- and macrovascular complications.  For optimum control of BP two or more drugs are usually needed in diabetic patients.  ACEIs or ARBs alone or in combination is superior than any other antihypertensive in diabetic population and should be started early so as to retard the progression of nephropathy.  Besides glycemic control and BP control, the issues of dyslipidemia and microalbuminuria also should be considered.  Lifestyle modifications are prescribed for all diabetic hypertensives. Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

Review Article Suggested Reading 1. Tarnow L, Rossing P, Gall MA, et al. Prevalence of arterial hypertension in diabetic patients before and after the JNC V. Diabetes Care 1994;17:1247-51. 2. Patel JC. Diabetes and its complications. J Diab Assoc India 1985;25:16-23. 3. Murray CJ, Lopez AD. Mortality by cause for eight regions of the world. Global Burden of Disease Study. Lancet 1997;349:1269-76. 4. Das S. Etiopathogenesis of hypertension in diabetics. Int J Diab Dev Ctries 1995;15:106-9. 5. Anonymous. The Sixth Report of the JNC on Prevention, Detection, Evaluation and Treatment of High BP. NIH Publication 1997;98(4080):1-68. 6. Deedwania PC. Hypertension and diabetes: new therapeutic options. Arch Intern Med 2000;160: 1585-94. 7. Mehtha DK, Martin J, Jordan B, Macfarlane CR. British National Formulary 43. Br Med Ass 2002;43:95‑7. 8. Rajmohan L, Mohan V. Repaglinide the prandial glucose regulator: a new class of oral antidiabetic drugs.

Thakur BB, (Ed.), Medicine - Update, APICON 2000;10:519‑21. 9. Paul B, Sapra B, Maheswari S, et al. Role of losartan treatment in the management of diabetic hypertension. J Assoc Physician India 2000:48:514-7. 10. Kumar S. RAAS in diabetes: therapeutic options. In: Clinical Medicine Update. Chug S (Ed.), South Asia Publishers Pvt.Ltd., New Delhi 2002;5:93-8. 11. Stanton A. ABCD Study. Calcium channel blockers. BMJ 1998;316:1471-3. 12. Harsson I, Zanchetti A, Carruthers SG, et al. Effect of intensive BP lowering and low dose aspirin in patients with HT: principal results of the HOT randomized trial. Lancet 1998;351:1755-62. 13. The Diabetic Control and Complication Trial Research group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in IDDM. N Engl J Med 193;329: 977-86.

...Cont’d from page 39... 31. Anderson JH Jr, Brunelle RL, Keohane P, Koivisto VA, Trautmann ME, Vignati L, et al. Mealtime treatment with insulin analog improves postprandial hyperglycemia with hypoglycemia in patients with non-insulin dependent diabetes mellitus. Multicenter Insulin Lispro Study Group. Arch Intern Med 1997;157(11):1249-55. 32. Seshiah V, Balaji V, Balaji MS. Insulin aspart - safe during pregnancy. Diabetes Care 2006;54(Suppl 1):A133. 33. Prasad S, Prasad GM. Maternal and perinatal outcome in using insulin aspart versus regular insulin in gestational diabetes mellitus. Diab Care 2008;57(Suppl 1):A581. 34. Hod M, Visser G, Damm P, et al. Safety and perinatal outcome in pregnancy: a randomized trial comparing insulin aspart with human insulin and 322 subjects with type 1 diabetes. Diabetes 2006;55(1):A417. 35. Mathiesen ER, Kinsley B, Amiel SA, et al. Maternal hypoglycemia and glycemic control in pregnancy: a randomized trial comparing insulin aspart with human insulin and 322 subjects with type 1 diabetes. Diabetes 2006;55(Suppl 1):A40.

36. Pettitt DJ, Ospina P, KolaczynskI JW, Jovanovic L. Comparison of an insulin analog, insulin aspart, and regular human insulin with no insulin in gestational diabetes mellitus. Diabetes Care 2003;26(1):183-6. 37. Jovanovic L, Pettitt DJ. Treatment with insulin and its analogs in pregnancies complicated by diabetes. Diabetes Care 2007;30(2):S220-4. 38. Haruo N, Mitsuyo S, Koji M, Makoto O, Ikuko H, Hideshi K. Does multiple injection therapy (MIT) with an ultrarapid-acting insulin analogue prevent cardiovascular disease in type 2 diabetes? The NICEStudy: a prospective, randomised, open-label, blinded endpoint study. ADA 68th Scientific Sessions 2008, Abstract Number: 163-OR. 39. Diamond T, Kormas N. Possible adverse fetal effects of insulin lispro. N Engl J Med 1997;337(14):1009; author reply 1010. 40. Halimi S, Raskin P, Liebl A, Kawamori R, Fulcher G, Yan G. Efficacy of biphasic insulin aspart in patients with type 2 diabetes. Clin Ther 2005;27(Suppl B): S57-74.

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review article

Headache â&#x20AC;&#x201C; A Review Uma Garg*, MK Garg**

Abstract According to IHS (International Headache Society) headache may be divided into two types - Primary or Benign headache and Secondary or Organic headache. Truly speaking most of the headaches are primary and very rarely we encounter secondary headaches. Key words: Benign headache, organic headache, migraine, sinus headache

eadache is a very common presenting symptom in all the clinics whether general or specialty. It is a fundamental component of human biology. Most of us if not all have physiologic potential for headache. The over all life time incidence of headache is 90-100% (in young females - 100%). Headache accounts for 20% of absence at work place as a result of this sickness affecting quality-of-life. Migraine is the commonest cause of headache evaluated so far, much more common than we think of. Migraine effects 10-12% of general adult population. M:F is (1:3). Peak prevalence age is during 25-55 years. Other less common causes of headache are hypertension, headache of drug abuse and rarely brain tumors or intra cranial pathologies. Severity of headache does not point towards any diagnosis. The duration and pattern of occurrence and associated symptoms are more important diagnostic indicators. Generation of headache is undoubtedly at higher, central or brain level and whenever it perceives a threat of any kind as a part of protective physiology it reflects as headache. A wide range of triggering factors which may be central or peripheral may initiate the process. According to IHS (International Headache Society) headache may be divided into two types - Primary or

*Associate Professor and Head Dept. of ENT **Associate Professor and Head Dept. of Surgery Muzaffarnagar Medical College and Hospital, Muzaffarnagar Address for correspondence Dr Uma Garg Associate Professor and Head, Dept. of ENT Muzaffarnagar Medical College and Hospital, Muzaffarnagar E-mail: drumamkgarg_1962@yahoo.co.in

benign headache and secondary or organic headache. Truly speaking most of the headaches are primary and very rarely we encounter secondary headaches1 (1 in 250,000 i.e. 0004%). Migraine and associated migrainous headaches including sinus problems constitute a major percentage of these primary headaches. The aim of this paper is to give an insight into the pathophysiology of headache thus pointing towards the important life-threatening sinister causes of headache and their management. Sinus headache, a poorly understood cousin of migraine needs to be differentiated clearly thereby indicating surgical treatment. Different descriptions of headache are seen in clinical practice e.g., a knife is continuously being pushed deep into my head or it seems like a ton of weight is lying on my head or whole of my L/R head is pounding. Pathophysiology Pathophysiology of headache is basically supported by hypothesis of neurovascular dysfunction of trigeminal nervous system. Head is supplied by all three branches of trigeminal nerve and upper cervical nerves i.e. greater and lesser occipital nerves. The latter supply posterior aspect of head, neck and upper shoulders. Sensory afferents from these areas have their first central synapse in trigeminal caudate nucleus (TCN).1 From here, second order neurons supply parasympathetic tracts. This in turn leads to activation of the of Trigemino vascular system releasing neuropeptides e.g., CGRP, substance - P and neurokinin - A from trigeminalafferents innervating vascular and other structures within the trigeminal distribution. With this, the Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

Review Article parasympathetic tracts innervating the sinus cavities are also stimulated producing rhinorrhea, lacrimation, nasal congestion and facial pain or heaviness. Any offending agent/irritation of nasal mucosa i.e. cold, hot, dust, allergens, chemicals, regional immunologic, infectious anatomic factors may activate the trigemino neurovascular system via TCN and initiate the release of vasodilators leading to headache. This is how headache is also explained in rhinosinusitis. Anything disrupting, irritating the path ways between TCN and upper neck and shoulders can trigger the mechanism. Etiology may be different but ultimate what we get is headache. This is known as convergence hypothesis.2 It is important to note here that many a times there is no recognizable triggering factor. A possible correlation has also been hypothesized between migraine and retinal microvasculature. Retinal and cerebral microcirculation share similar anatomical, embryological, physiological and neurovascular mechanisms. Therefore, a definite association exists between migraine and increased prevalence of retinopathies in middle aged individuals. Retinal microvasculature abnormalities and migraine both have been consistently linked with clinical and subclinical stroke.3 Ultra structural studies show ↓↓sed cerebral magnesium levels, mitochondrial abnormalities leading to ↓O2,↑sed No. levels and P/Q-associated calcium channelopathies. These all are causes of hyperexcitability of the brain eventually leading to migraine.4 Causes  Primary  Secondary - Various metabolic, traumatic, inflammatory, neoplastic, endocrinal, immunologic and vascular causes are described. Some of them are migrainous, ergotamine dependent headache,5 chronic paroxysmal hemicrania, cerebral tumor,5 benign intracranial hypertension, cerebral aneurysm,5 temporal arteritis, meningitis, cough headache, TMJ dysfunction, cervical headache, sinus headache, headache of herpes, headache of depression and many others.

or irregularly. It is unilateral, throbbing and moderate to severe in intensity and aggravated by activity, light or sound. To diagnose migraine, the subject must give history of H/O at least 5 attacks of headache of 4-72 hours of duration if untreated. No secondary cause is found. Nausea, vomiting, phonophobia, photophobia and lacrimation may accompany the event. Aura may be there with varying disability. Other Migrainous Headache Include tension headache or cluster headache. These may be bilateral, less disabling and are not usually aggravated by activity. These are no associated features.  Ergotamine dependent headache is seen in those migraine subjects who take ergotamine as soon as they think that migraine is coming as prophylactic treatment. But repeated intake leads to more frequent headache not responding to migraine.  CPH: Rare form of U/L headache. Common in men and responds to indomethacin.  Cerebral tumor: A rare cause of headache, much rare than commonly though of. It needs a cluster of symptoms to diagnose a cerebral tumor.  Benign intracranial hypertension: Rarer, S/S of raised intracranial pressure are present.  Cerebral aneurysm: Is a vascular catastrophe, sudden severe pain radiating to neck exacerbated by head and neck movements. Sometimes a dull unilateral headache may be present for several weeks. CT may be inconclusive at this stage of aneurysmal expansion. DSA may be helpful.  Temporal arteritis: Presents with temporal headache which may not be severe. Steroids can be started early while waiting for arterial biopsy results.  Meningitis: Fever, severe headache, neck stiffness and drowsiness suggest diagnosis. CSF picture distinguishes from other causes.  Cough headache: This is different from headache of raised intracranial pressure aggravated by coughing. This is benign and has got a limited natural history improving slowly on its own.

Migraine

Management  Investigations  Treatment

It is a common, chronic, incapacitating paroxysmal disorder with attacks of headache recurring regularly

There are three important aspects of evaluation of headache history, history and the history.

Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

Review Article 



History: About duration, onset, pattern, change in type, associated features, H/O of smoking/ alcohol. Examination: G/E, CVS, fundus examination, ENT examination (especially for sinusitis). Investigations: a) LAB n Complete hemogram n Blood sugar levels n ECG n LP b) Radiological AP Skull

X-ray

Water’s view (OM) Last view

Figure 1.

Treatment If Migraine: Therapy of migraine is directed towards control of the:  Acute attacks  Prophylactic - In between the attacks  Behavioral therapy  Surgical Acute Therapy

Aim is to achieve rapid relief from symptoms and reduce disability. A simple plan for acute treatment is: At zero hours: Simple analgesics e.g., PCM (1000 mg), aspirin (600 mg), NSAIDs like ibuprofen (400-800 mg), tolfenamic acid, naproxen sodium, diclofenac suppository (100 mg). Two hours: Combination therapy antiemetics like domperidone (20 mg)

along

with

Four hours: Triptans are given e.g., (Sumatriptan, Naratriptan, Rizatriptan). Triptans are not given during aura. Medical therapy for igraine could be started in preheadache period and can be continued in postheadache period for better results. 18

Sumatriptan is a faster acting triptan and can be used with a triptan having long half life in those who have headache recurrence following triptan therapy. Dosage - Sumatriptan 50 mg6; Rizatriptan 5-10 mg. Other triptans include frovatriptan, almotriptan, zolmitriptan and eletriptan. (2) IM Diclofenac (75 mg) with IM metoclopramide. The problem with the opiates is addiction. Prophylactic

Base of skull PNS

CT MRI

Lateral view

Rescue therapy - (1) for those not responding to above medication. It includes subcutaneous sumatriptan (5 mg), butorphenol spray, parenteral phenothiazines, nasal sumatriptan and nasal zolmitriptan.

Needs to be considered in following situations:  Frequent headache >2/week or 3 attacks/month.  Interference with daily routine as attacks are very severe.  Failure of acute therapy or CI or adverse side effects.  Presence of associated or complicating conditions with e.g., n Hemiplegic migraine7 n Basilar migraine7 n Migraine with prolonged aura n Migrainous infarction Medication should atleast be given for three months. Various drugs for Prophylaxis are:  b-blockers: propranolol, timolol, metoprolol, tiagabine, atenolol  Levatiracetam, zonisamide  Anticonvulsant divalproex, topiramide, gabapentin.8 Sodium valproate (400-1,500 mg/day)  TCA- When frequency more and intensity less. Amitryptiline 50-100 daily  5HT antagonists - Pizotifen (Single bed time dose) 1.5-3.0 mg daily  Serotonin antagonists 

Botulinum toxin9



Riboflavin10



Magnesium



Montelukast11

{

Acute Prophylactic

Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

Review Article Management Algorithm for Sinus Headache

Sinus Headache

Evaluate HA pattern

New onset or change In existing HA pattern

Assess for Underlying disease

Evaluation positive: Evaluate and treat as directed by medical evaluation

Evaluation Normal: Consider presumptive diagnosis of major complaint Primary HA

Stable HA pattern >6 months

Episodic pattern <15 days/month

Chronic pattern <15 days/month

Headache is major complaint

HA is a component of other sinus symptoms

Presumptive of migraine

ENT evaluation

Positive Tx underlying pathology

Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

Evaluate for medication overuse (>2 days/week)

If present: Stop rebounding medicines

If absent: Try different acute HA medicine

Negative Tx symptomatically New or different preventive, schedule followup and consider HA consultation

Review Article 

Lisinopril



CGRP BIBN 4096 BS



Tizanidine



Phytotherapy



Acupuncture



Flunarizine



Among all these flunarizine has been found to be most effective for headache occurring at night sleep. (It is a calcium channel blocker). Behavioral Therapy 

Regular meals



Avoidance of alcohol, fizzy drinks, OC’s



Regular sleep and exercise preferably



Avoid glare, stress, travel



Maintain headache diary

Try three different strategies in succession before embarking on decision to refer the patient to a neurologist. If the patient does not fit into migraine it may be:

{

Tension Cluster Cervicogenic

Surgical

If battery of investigations reveals a surgically treatable cause then surgery is indicated e.g., sinusitis, cerebral tumors. Whether acute/prophylactic, assurance with explanation is best treatment. Flag Signs  Headache which builds up apoplectically with in a few seconds.  Headache beginning abruptly with strenuous exertion.  Headache associated with neck pain (meningismus).  Headache radiating to back of neck (cerebral aneurysm).  Headache-associated with neurological symptoms (SAH).12  Headache associated with ophthalmic symptoms (Pituitary).13 20

Headache-associated with menstrual disturbances (pituitary).13 Headache not confirming to any of the primary headaches.14 Headache similar to a headache long back in past which has been forgotten. The first worst headache ever experienced before and lands the patient in emergency hospital.

Conclusion  Mostly headaches are primary and migrainous even sinus headache.  Prophylactic treatment is better and more result fetching than acute cases.  Exclusion of secondary causes is mandatory keeping in mind the flag signs. Sinus headache is considered a subclass in migrainous headaches because these both share the same pathway, same symptoms, same triggering factors and response to sumatriptan. In sinusitis, headache is more in those subjects who are more prone to migraine. So the headache which seems to be sinus headache can be treated medically. Surgical treatment is reserved for the cases which do not respond to medical treatment.  Fear of stroke i.e. ischemic stroke is ↑sed especially in females who take OC’s or who smoke. PS if patient primarily presents predominantly with headache and nasal symptoms are in the midst of associated migraine symptoms as nausea and photophobia likely diagnosis is migraine. Patient c/o pain not very severe and nasal symptoms e.g., nasal pain, obstruction/purulence are prominent-sinusitis and migraine can coexist comorbidly. References 1. Cady RK, Schreiber CP. Sinus headache: a clinical conundrum. OCNA 2004;37:267-88. 2. Which Headache. A guide to the diagnosis and management of headache. Worthing (UK): Professional Postgraduate services Eurpe Ltd., 1991. 3. Retinal Vascular Caliber and Migraine: The Blue Maintain Eye study Grald Liew, Poul Mitchell, Tien Yin Wong, Jie Jin Wang. 4. Welch KM, Ramadan NM. Mitochondria, magnesium and migraine. J Neurol Sci 1995;134:9-14.

Cont’d on page 58... Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

review article

Postprandial Hyperglycemia, Implications and Control SR Aravind

Abstract A growing body of evidence suggests that reducing postmeal plasma glucose excursions is as important, or perhaps more important for achieving HbA1C goals. If tight control has to be achieved, PPG control is mandatory. PPG excursions are linked to endothelial dysfunction and atherogenesis resulting in higher cardiovascular morbidity and mortality. Key words: HbA1C, fasting plasma glucose, postmeal plasma glucose excursions

Glycemic Targets in Type 2 Diabetes For patients with type 2 diabetes mellitus (T2DM), the American Diabetes Association (ADA) recommends a target A1C level <7.0% and a fasting plasma glucose (FPG) level between 70 and 130 mg/dl.1 In clinical practice, the major focus of treatment has been on lowering glycosylated hemoglobin (HbA1C) levels, with a strong emphasis on FPG. Although control of FPG is necessary, it is often insufficient to obtain optimal glycemic control. A growing body of evidence suggests that reducing postmeal plasma glucose excursions is as important, or perhaps more important for achieving HbA1C goals. To address this issue, the International Diabetes Federation (IDF) has published a guideline that reviews the evidence on the harmful effects of elevated postmeal glucose and makes recommendations on treatment of postmeal glucose.2 Importance of Postprandial Glucose Because T2DM is often diagnosed based on FPG level and patientâ&#x20AC;&#x2122;s A1C at diagnosis is 8%-9% or higher, the initial focus of treatment is on FPG. Research has found that at A1C levels of <8.5%, PPG begins to become the major determinant of the A1C level. In fact, as the A1C level falls to <7.3%, it is estimated that Director, Diacon Hospital Course Director: Certificate course in Diabetology (RGUHS) Visiting Professor, Dept. of Medicine, PESIMSR, Kuppam Past Chairman, Scientific Committee, RSSDI - 2010 Past Chairman, KRSSDI, Vice President, Diabetes India Exe. Committee Member, RSSDI Patron, Diabetes Club, Bangalore E-mail: draravind@hotmail.com/diaconhospital@hotmail.com

Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

postprandial glucose (PPG) contributes approximately 70% to the magnitude of the A1C level.3 Even in the natural history of type 2 diabetes, PPG is affected initially due to defect in first phase insulin secretion following any glucose challenge. FPG is affected late in the course of pathophysiology when the insulin secretion is considerably low.4 A meta-analysis of the Whitehall, Paris Prospective and Helsinki Policemen studies,5 the Chicago Heart Association Detection Project in Industry Study6 and the Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe (DECODE) study7 all provide evidence for emerging potential correlation of PPG excursions with increased cardiovascular disease (CVD) mortality.7 The mechanism whereby elevated PPG exerts its effects on atherogenesis is still evolving, but it may be through a negative impact on endothelial function.8,9 PPG peaks have been directly associated with increased intima-media thickness, with a reduced endothelial-dependent flow mediated dilation indicating a decrease in nitric oxide production in type 2 diabetic patients indicative of an increased atherosclerotic risk.10 Nonetheless, because of its contribution to glycemia and the A1C level as well as atherogenesis, the importance of achieving PPG targets is clear. Postprandial Glucose Excursions: Indian Context The higher glucose load, having higher glycemic index, in the Indo-Chinese diets lead to greater prandial glycemic excursion, increased glucosidase and incretin activity in the gut and may need special therapeutic strategies to tackle these glucose peaks. Thus a typical 21

Review Article Indo-Chinese postmeal glucose curve has wider glycemicexcursion as well as greater postprandial load which leads to higher lipemic peaks and has epidemiological links to CVD.11 PPG Excursions and Gestational Diabetes Mellitus The most significant neonatal complication associated with gestational diabetes mellitus (GDM) is macrosomia. The risk of macrosomia increases with increasing postprandial hyperglycemia.12-14 Studies have documented that the peak glucose concentration occurs one hour after eating. Improved fetal outcome and less risk of neonatal hypoglycemia, macrosomia and cesarean delivery occurred in GDM managed by controlling PPG concentration.15 Options for Treating Postprandial Excursions Lifestyle Interventions to Reduce PPG

Lifestyle interventions remain a cornerstone of therapy for lowering PPG in T2DM. In a 3-year randomized controlled study of lifestyle interventions, including dietary modification and exercise, after one year, PPG levels decreased 11 mg/dl in the lifestyle intervention group and increased 7 mg/dl in the control group. After three years, a sustained reduction of the PPG level was observed, but only in the 72% (106/147) who completed the 3-year study.16 Pharmacologic Options to Reduce PPG

The α-glucosidase inhibitors are effective in lowering PPG because they delay carbohydrate absorption, with one meta-analysis reporting mean reductions of 42 and 49 mg/dl for acarbose and miglitol, respectively.17 They have the added advantage of being weight-neutral; however, gastrointestinal side effects often limit patient acceptance. The glinides are another option. Repaglinide has been shown to provide a similar reduction in PPG (p = 0.07) compared with glyburide after 14 weeks in 195 patients with T2DM.18 Compared with glimepiride 2 mg oncedaily, repaglinide 1 mg twice-daily has been shown to provide a significantly greater reduction in PPG following a standard meal (n = 14).19 An 8-week study 22

involving 101 patients showed similar reduction of PPG with nateglinide 120 mg thrice-daily and glyburide 10 mg once-daily following a standard meal.20 Direct comparison of repaglinide and nateglinide shows comparable reduction in PPG.21-23 Other options include the oral dipeptidyl peptidase-4 (DPP-4) inhibitors - sitagliptin24 and saxagliptin.25 In addition, injectable agents are also effective in lowering PPG. These include the glucagon-like peptide-1 (GLP-1) agonists - exenatide26 and liraglutide;27 the amylin analogs - pramlintide28 and prandial insulin.13 An advantage of the GLP-1 agonists is that they promote weight loss. Pramlintide is approved only for use in conjunction with prandial insulin.29 Insulin Therapy and PPG Excursions

Basal insulin is a common start insulin. However, it must be recognized that control of PPG is less likely with basal insulin than with prandial insulin. From a physiologic viewpoint, prandial/premixed (mealtime or bolus) insulin would be the best choice if the plan is to target PPG and to continue the oral agents (metformin and pioglitazone). Short-acting insulins specifically address postprandial hyperglycemia when given in a meal-adapted manner. regular human insulin (RHI) has a maximal action approximately two hours after injection and duration of action of approximately 6-8 hours, depending on the dose injected. The fast-acting insulin analogs like aspart and lispro were developed to mimic the physiological insulin response after a meal with a better action profile than RHI and can also be used for prandial insulin therapy.30,31 Rapid-acting Insulin Analogs

Insulin aspart: It was approved for clinical use in 1999. Insulin aspart is made by a structural modification wherein proline in B28 position is replaced with negatively charged aspartic acid which offers an ultrashort-acting pharmacokinetic property to it. Efficacy and safety in pregnancy has been proved in several clinical studies across the world including India.32-38 Insulin lispro: In this insulin, amino acids, lysine and proline, respectively at 29th and 28th position in the β chain are swapped. The pharmacokinetic profile of Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

Review Article lispro is similar to that of aspart. Anecdotal studies of lispro in pregnancy have shown better efficacy and safety than RHI; however, use of insulin lispro in preGDM is still a concern though the teratogenicity has not been conclusively established. Lispro is category B drug in the US FDA list.39 Biphasic Insulins

α-glucosidase inhibitors, glinides, human short-acting insulin, short-acting analogs, DPP-4 inhibitors and GLP-1-based therapies, short-acting sulfonylureas. Among all the available options, rapid-acting analogs and biphasic insulin analogs provide the best PPG control with least amount of hypoglycemia and weight gain. Its unique formulation and pharmacokinetic actions make this possible.

Rapid-acting premixed insulin analogs such as biphasic insulin aspart 30 (BIAsp 30 [30% soluble insulin aspart and 70% protamine-crystallized insulin aspart] and LisproMix (25% soluble Lispro and 75% protaminated Lispro) have recently been developed to overcome the pharmacokinetic limitations of RHI used in the most commonly prescribed premix, biphasic human insulin 30 (BHI 30, 30% human insulin and 70% neutral protamine Hagedorn [NPH] insulin). One study reported a greater lowering of postprandial triglyceride levels with BIAsp 30 than with BHI 30.40

References

The story of glucose control does not end with insulin, but monitoring control is also of paramount importance. It should include frequent monitoring of blood glucose levels with an aim to achieve normoglycemia without significant hypoglycemia. In all these cases, FPG and PPG levels should be measured regularly and self-monitoring of blood glucose (SMBG) should be emphasized upon. Careful monitoring and dose adjustments are required towards the end of pregnancy, labor and after delivery as during this time insulin requirements undergo several changes.

4. Das AK, Varma RS. Monitoring and natural history of post-prandial hyperglycemia. J Assoc Physicians India 2001;49(Spec No):7-10.

Summary

7. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. The DECODE study group. European Diabetes Epidemiology Group. Diabetes Epidemiology: Collaborative analysis of Diagnostic criteria in Europe. Lancet 1999;354(9179):617-21.

Contribution of PPG is important for HbA1C values <8.5. If tight control has to be achieved, PPG control is mandatory. PPG excursions are linked to endothelial dysfunction and atherogenesis resulting in higher cardiovascular morbidity and mortality. Traditional South East Asian diet has a high carbohydrate load, which results in higher PPG excursions. PPG excursions are linked to higher fetal abnormalities in pregnancies complicated by impaired glucose tolerance. Lifestyle modification is a must in all patients. This includes dietary and exercise advice on an individual basis. Among the drugs available for PPG control, following can be chosen based on the evidence: Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

1. American Diabetes Association. Standards of medical care in diabetes - 2010. Diabetes Care 2010;33 (Suppl 1):S11-61. 2. Guideline for management of postmeal glucose. International Diabetes Federation 2007. 3. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c). Diabetes Care 2003;26(3):881-5.

5. Balkau B, Shipley M, Jarrett RJ, Pyörälä K, Pyörälä M, Forhan A, et al. High blood glucose concentration is a risk factor for mortality in middle-aged nondiabetic men. 20-year follow-up in the Whitehall Study, the Paris Prospective Study, and the Helsinki Policemen Study. Diabetes Care 1998;21(3):360-7. 6. Lowe LP, Liu K, Greenland P, Metzger BE, Dyer AR, Stamler J. Diabetes, asymptomatic hyperglycemia, and 22-year mortality in black and white men. The Chicago Heart Association Detection Project in Industry Study. Diabetes Care 1997;20(2):163-9.

8. Esposito K, Giugliano D, Nappo F, Marfella R; Companion Postprandial Hyperglycemia Study Group. Regression of carotid atherosclerosis by control of postprandial hyperglycemia in type 2 diabetes mellitus. Circulation 2004;110(2):214-9. 9. Iijima R, Nakajima R, Sugi K, Nakamura M. Improvement of postprandial hyperglycemia has a positive impact on epicardial flow of entire coronary tree in acute coronary syndromes patients. Circ J 2007;71(7):1079-85.

Review Article 10. Siervo M, Corander M, Stranges S, Bluck L. Postchallenge hyperglycaemia, nitric oxide production and endothelial dysfunction: the putative role of asymmetric dimethylarginine (ADMA). Nutr Metab Cardiovasc Dis 2011;21(1):1-10. 11. Joshi SR, Karne R. Pre-diabetes, dysglycaemia and early glucose intolerance and vascular health. J Assoc Physicians India 2007;55:829-31. 12. Langer O, Mazze R. The relationship between largefor-gestational age infants and glycemic control in women with gestational diabetes. Am J Obstet Gynecol 1988;159(6):1478-83. 13. Jovanovic-Peterson L, Peterson CM, Reed GF, Metzger BE, Mills JL, Knopp RH, et al. Maternal postprandial glucose levels and infant birth weight: the Diabetes in Early Pregnancy Study. The National Institute of Child Health and Human Development – Diabetes in Early Pregnancy Study. Am J Obstet Gynecol 1991;164 (1 Pt 1):103-11. 14. Combs CA, Gunderson E, Kitzmiller JL, Gavin LA, Main EK. Relationship of fetal macrosomia to maternal postprandial glucose control during pregnancy. Diabetes Care 1992;15(10):1251-7. 15. de Veciana M, Major CA, Morgan MA, Asrat T, Toohey JS, Lien JM, et al. Postprandial versus preprandial blood glucose monitoring in women with gestational diabetes mellitus requiring insulin therapy. N Engl J Med 1995;333(19):1237-41. 16. Roumen C, Corpeleijn E, Feskens EJ, Mensink M, Saris WH, Blaak EE. Impact of 3-year lifestyle intervention on postprandial glucose metabolism: the SLIM study. Diabet Med 2008;25(5):597-605. 17. Van de Laar FA, Lucassen PL, Akkermans RP, Van de Lisdonk EH, Rutten GE, Van Weel C. Alpha-glucosidase inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev 2005;(2):CD003639. 18. Landgraf R, Bilo HJ, Müller PG. A comparison of repaglinide and glibenclamide in the treatment of type 2 diabetic patients previously treated with sulphonylureas. Eur J Clin Pharmacol 1999;55(3):165-71. 19. Rizzo MR, Barbieri M, Grella R, Passariello N, Barone M, Paolisso G. Repaglinide is more efficient than glimepiride on insulin secretion and post-prandial glucose excursions in patients with type 2 diabetes. A short term study. Diabetes Metab 2004;30(1):81-9. 20. Hollander PA, Schwartz SL, Gatlin MR, Haas SJ, Zheng H, Foley JE, et al. Importance of early insulin secretion: comparison of nateglinide and glyburide in previously diet-treated patients with type 2 diabetes. Diabetes Care 2001;24(6):983-8.

21. Li J, Tian H, Li Q, Wang N, Wu T, Liu Y, et al. Improvement of insulin sensitivity and beta-cell function by nateglinide and repaglinide in type 2 diabetic patients: a randomized controlled double-blind and doubledummy multicentre clinical trial. Diabetes Obes Metab 2007;9(4):558-65. 22. Rosenstock J, Hassman DR, Madder RD, Brazinsky SA, Farrell J, Khutoryansky N, et al; Repaglinide Versus Nateglinide Comparison Study Group. Repaglinide versus nateglinide monotherapy: a randomized, multicenter study. Diabetes Care 2004;27(6):1265-70. 23. Charbonnel B, Karasik A, Liu J, Wu M, Meininger G; Sitagliptin Study 020 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care 2006;2(12):2638-43. 24. Rosenstock J, Sankoh S, List JF. Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetes. Diabetes Obes Metab 2008;10(5):376-86. 25. Linnebjerg H, Park S, Kothare PA, Trautmann ME, Mace K, Fineman M, et al. Effect of exenatide on gastric emptying and relationship to postprandial glycemia in type 2 diabetes. Regul Pept 2008;151(1-3):123-9. 26. Schwartz SL, Ratner RE, Kim DD, Qu Y, Fechner LL, Lenox SM, et al. Effect of exenatide on 24-hour blood glucose profile compared with placebo in patients with type 2 diabetes: a randomized, double-blind, two-arm, parallel-group, placebo-controlled, 2-week study. Clin Ther 2008;30(5):858-67. 27. Marre M, Shaw J, Brändle M, Bebakar WM, Kamaruddin NA, Strand J, et al; LEAD-1 SU study group. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU). Diabet Med 2009;26(3):268-78. 28. Thompson RG, Gottlieb A, Organ K, Koda J, Kisicki J, Kolterman OG. Pramlintide: a human amylin analogue reduced postprandial plasma glucose, insulin, and C-peptide concentrations in patients with type 2 diabetes. Diabet Med 1997;14(7):547-55. 29. Symlin prescribing information. San Diego, CA: Amylin Pharmaceuticals, Inc.; 2008. 30. Lindholm A, McEwen J, Riis AP. Improved postprandial glycemic control with insulin aspart: a randomized double-blind crossover trial in type 1 diabetes. Diabetes Care 1999;22(5):801-5.

Cont’d on page 48...

Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

review article

Anemia of Chronic Disease and Periodontitis: The Missing Link Nithya Anand*, SC Chandrasekar**, Garima Dembla†

Abstract Anemia of chronic disease (ACD), the second most prevalent form of anemia after iron deficiency anemia, is a condition associated with chronic diseases. Increasingly referred to as ‘Anemia of inflammation’, this type of anemia is to a large extent immune driven and cytokine mediated. This article reviews the various factors interlinking periodontitis, a chronic inflammatory condition with the pathogenesis of ACD. Key words: Anemia of chronic disease, cytokine-mediated, periodontitis

nemia of chronic disease (ACD) defined as the anemia occurring in chronic infections and inflammatory conditions is not due to marrow deficiencies or other diseases and occurs in the presence of adequate iron stores and vitamins.¹ The ACD is a prevalent, poorly understood condition that afflicts patients with a wide variety of diseases, including infections, malignancies and rheumatologic disorders. It is characterized by blunted erythropoietin response by erythroid precursors, decreased red blood cell survival and a defect in iron absorption and macrophage iron retention, which interrupts iron delivery to erythroid precursor cells. Pathogenesis of Anemia of Chronic Disease Cartwright (1966) postulated the three pathologic processes involved in ACD:  



Shortened erythrocyte survival Failure of the bone marrow to increase red blood cells production to compensate for this increased demand Impaired release of iron from the reticuloendothelial system.²

*Reader **Head † Postgraduate Student Dept. of Periodontics Sree Balaji Dental College and Hospital, Bharath University, Chennai Address for correspondence Dr Nithya Anand E-mail: nitan10@gmail.com

Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

The low serum iron and accumulation of iron in the reticuloendothelial cells of the patient is the result from the retention of iron by reticuloendothelial macrophages and decreased intestinal iron absorption. This impairment of iron delivery by macrophages and enterocytes is the part of a host defence mechanism to fight infection and cancer. Early in their course, patients with the anemia of chronic disease have normal body iron stores and a mild normocytic anemia that results from impaired iron cycling. Over time the impaired intestinal iron absorption associated with anemia of chronic disease leads to iron deficiency and the anemia becomes microcytic. Cytokines such as interleukin-1 (IL-1), IL-6, tumor necrosis factor-alpha (TNF-α) and interferons are hypothesized to be involved in the maintenance of red blood cell production or stability.³ Inflammation and Acute Phase Response Acute inflammatory disease is classically accompanied by signs and symptoms such as fever, anorexia and somnolence. The endocrine and metabolic response to acute inflammation includes the release of hormones which induce catabolism and gluconeogenesis such as glucagon, insulin, adrenocorticotropic hormone, growth hormone, thyroxine and catecholamines. The concentrations of iron and zinc in plasma decrease while those of copper increase. The hematopoietic response includes leukocytosis, thrombocytosis and anemia secondary to decreased erythropoiesis.4 Surgical trauma induces a state of inflammation with an acute-phase reaction and anemia. The severity of this response is related to the extent of trauma. When 25

Review Article the hemoglobin (Hb) concentration acutely decreases in patients with normal renal function, erythropoietin secretion is increased for 4-10 days. The reactive increase in erythropoietin secretion is diminished in patients undergoing an acute-phase response which has been attributed to inhibition of erythropoietin secretion by pro-inflammatory cytokines. A narrow definition of the acute-phase response to inflammation is based on the characteristic changes in the concentrations of several plasma proteins secondary to altered hepatic transcription and synthesis of excretory proteins. The plasma concentrations of the two major human acute-phase proteins, C-reactive protein (CRP) and serum amyloidal A, increase 100-1,000 fold in response to severe infections. The concentrations of other positive acute-phase proteins increases less e.g., complement factors, fibrinogen, ferritin, haptoglobin and α1 protease inhibitor. Among the negative acute-phase synthesis and secretion is decreased are albumin, transferrin, α-fetoprotein and transthyretin. The acute-phase response is regulated by a number of pro-inflammatory cytokines such as IL-1, TNF-α, IL-6, β- and γ-interferon. The cytokines are to a large extent produced locally by tissue macrophages, but in severe inflammation, systemic effects occur as well. Periodontitis: An Inflammatory Disease Periodontitis is an inflammatory disease of the supporting tissues of the tooth which is caused by specific micro-organisms in a susceptible host. Gram-negative anaerobic bacteria are most commonly associated with the initiation of periodontitis. The bacteria and their products evoke an immunoinflammatory reaction in the host tissue. Though this process is intended to eliminate the microbial challenge, it often results in damage to the host tissue. The sulcular epithelium acts as a protective barrier and prevents entry of micro-organisms and other irritants into the systemic circulation. The host-microbial interaction in periodontitis leads to ulceration of sulcular epithelium. The ulcerated epithelium acts as a portal of entry for the bacteria to enter the connective tissue and thus into the systemic circulation. Bacteremia has been observed in patients with periodontitis and has been directly related to the severity of inflammation. The subgingival microbiota in patients 26

with periodontitis poses a significant and persistent gram-negative bacterial challenge to the host. Acutephase proteins like the CRP has been shown to be elevated in patients with periodontitis. This suggests a possible influence of periodontitis on systemic status of an individual. Studies have associated periodontitis with atherosclerosis, cardiovascular diseases and stroke. These studies indicate that periodontitis leads to a low grade systemic inflammation. Anemia of Inflammation: The Cytokinehepcidin Link The anemia of inflammation, commonly observed in patients with chronic infections, malignancy, trauma and inflammatory disorders, is a well-know clinical entity. It now appears that the inflammatory cytokine IL-6 induces production of hepcidin, an ironregulatory hormone that may be responsible for most or all of the features of this disorder. Hepcidin: The Iron Regulatory Hormone Hepcidin is a 20-, 22- or 25-amino acid peptide that is cleaved from a larger precursor. It is produced in the liver and detectable in the serum and urine.5 Hepcidin has intrinsic antimicrobial activity and its expression increases in response to inflammatory stimuli. Hepcidin was first isolated from human urine and named on the basis of its site of synthesis (hep) and its in vitro antibacterial properties (-cidin). In human urine, the predominant form contains 25-amino acids, although shorter 22 and 20 amino acid peptides are also present. The main peptide is notable for containing eight cysteine residues linked as four disulphide bridges resulting in a molecule with a simple hairpin structure is characteristic of peptides capable of disrupting bacterial membranes and is similar to other antimicrobial peptides.⁶ The existence of an iron regulatory hormone was postulated primarily to account for the observed interactions between the anatomically distinct sites of iron absorption, recycling and utilization. There was no indication that it had additional role in iron metabolism until 2001, when mouse studies were published showing that hepatic hepcidin mRNA synthesis was induced by iron loading. Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

Review Article Hepatic iron Fe/Tf

Hepcidin s

e kin

Inflammation Infection

Recycling Storage

Absorption

Induction of liver hepcidin synthesis decreases iron export from absorptive cells (enterocytes) recycling cells (macrophages) and storage cells (hepatocytes).

a hypoproliferative anemia by direct action on erythroid progenitor cells or indirectly by stimulating production. Despite the overall suppressive effect on erythropoiesis, some studies have shown that TNF-α and IL-1 stimulate the growth of early progenitors (burst forming units-erythroid [BFU-E]), while suppressing the growth of later stages (colony-forming units-erythroid [CFU-E]). The inhibitory effect of TNF-α and IL-1 on erythropoiesis can be overcome in a dose-dependent fashion by administering epoetin. Effects on Erythrocyte Survival

HFE and non-HFE hem [Not FP disease] Absorption Hepcidin

Recycling Storage

Anemia Hypoxia

Down-regulation of liver hepcidin synthesis increases iron export from absorptive cells (enterocytes) recycling cells (macrophages) and storage cells (hepatocytes).

Role of Hepcidin and IL-6 IL-6 acts directly on hepatocytes to stimulate hepcidin production. Hepcidin, in turn, acts as a negative regulator of intestinal iron absorption and macrophage iron release. Macrophage iron release

Inflammation

Macrophage

IL-6

Hepatocyte

Hepcidin Intestinal iron absorption

Effects on Erythropoiesis The erythropoiesis-suppressing effect of inflammation is mainly due to increased activity of the pro-inflammatory cytokines.⁷ In vivo, the cytokines act in concert to affect precursor cells at different stages of erythropoiesis. TNF-α and IL-1 are extensively studied. In experimental animal studies and in humans administration of both cytokines causes Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

Macrophages normally remove senescent erythrocytes from the circulation. Erythocytes coated with immunoglobulins or immune complexes are cleared more efficiently from the circulation.⁸ Macrophages, activated by inflammatory signals, are responsible for accelerated disposal of erythrocytes, shortening of the life-span of erythrocytes and decreasing the Hb concentration. Effects on Iron Metabolism Inflammation and the acute-phase response interact with iron metabolism at several levels. Inflammation reduces the serum concentrations of iron and transferrin. Kooistra et al found that iron absorption from the gut was impaired in patients with renal failure and elevated serum CRP levels (>8 mg/l). This is consistent with the notion that the synthesis of transferrin is reduced during the acute-phase response. Less apotransferrin is secreted in the bile and delivered to the gut. As a result less iron is delivered to the transferring receptors of the mucosal cells. Functional iron deficiency is defined as low availability of iron for erythropoiesis despite normal or high iron stores in the body. A state of functional iron deficiency often occurs when erythropoiesis is stimulated by erythropoietin, but the rate of iron delivery to the bone marrow is insufficient. Theoretically, functional iron deficiency may occur in one of the two ways:  When high doses of epoetin stimulate erythropoiesis so much that it exceeds the maximal capacity to deliver iron  When the delivery of iron from the reticuloendothelial cells to hematopoietic cells is inhibited or blocked. 27

Review Article Serum ferritin is an acute-phase protein and increases two- to four-fold in response to inflammation. IL-1 and TNF-α cause an increase in ferritin synthesis directly at the transcriptional level. Cytokines may also induce ferritin synthesis indirectly by increasing iron uptake into hepatocytes. The increase in ferritin synthesis by hepatocytes and reticuloendothelial cells underlies the increase in the iron storage pool during inflammation. The circulating ferritin contains only minute amounts of iron and its role in iron metabolism is uncertain. It may have protective detoxifying effect by taking up free iron at sites of inflammation. Lactoferrin is present in polymorphonuclear leukocytes and acts as an iron scavenger with bactericidal activity. As a part of the acute-phase reaction, lactoferrin synthesis increases during inflammation. It can bind large amounts of free iron. The iron bound to lactoferrin is taken up by activated macrophages, which express specific lactoferrin receptors. During inflammation, this causes iron deprivation of erythroid precursors, which fail to express lactoferrin receptors. Iron is essential for the growth of some microbes and sequestration of iron in the form of insoluble compounds, such as lactoferrin and hemosiderin is thought to be part of the host defence against bacterial and viral infections. However, a decrease in erythropoiesis may also reflect a relative deficit of erythropoiesis in the face of an increased demand to produce neutrophil granulocytes and other immunocompetent cells. Serum CRP Predicts Epoetin Resistance CRP is secreted by the liver and inflammation causes a rapid increase in its serum concentration. It plays a role in host defence by interacting with complement. It is simple, reliable readily available and in expensive test. It is also a long-term predicator of cardiovascular risk and mortality in the general population and in chronic renal failure patients. About one-third of patients with chronic renal failure have serum CRP concentrations >10 mg/l. In dialysis patients, high CRP levels are associated with low Hb levels and or epotein resistance Discussion Anemia is one of the most common global public health problem in recent times. Globally, anemia affects 1.62 billion people, which is 24.8% of the total population. Evidence indicates that ACD is seen in rheumatoid arthritis and chronic periodontitis, though 28

the etiologic factors of both the diseases are different, stating that long-standing chronic inflammation can lead to anemia. Various studies have found associations between ACD and periodontitis. The pro-inflammatory cytokines released in periodontitis interact with hepcidin the iron regulating hormone and down regulate erythropoiesis. Siegel et al reported a depression in the number of erythrocytes secondary to periodontal disease.⁹ Hutter et al suggested that periodontitis also needs to be considered as a chronic disease which may cause lower number of erythrocytes and consequently lower Hb levels.¹⁰ Conclusion The growing field of periodontal medicine has evidence interlinking periodontitis with cardiovascular disease, preterm low-birth-weight, diabetes and chronic obstructive pulmonary disease. The association between ACD and periodontitis with hepcidin being the key factor as new emerging concepts with wide reaching ramification needs more evidence and research. References 1. Sneha R, Sumanth S, Padhye AM. Evaluation of blood parameters in patients with chronic periodontitis for signs of anemia. J Periodontol 2010;81(8):1202-6. 2. Cartwright GE. The anemia of chronic disorders. Semin Hematol 1966;3(4):351-75. 3. Means RT Jr. The anemia of infection. Baillieres Best Pract Res Clin Haematol 2000;13(2):151-62. 4. Trey JE, Kushner I. The acute phase response and the hematopoietic system: the role of cytokines. Crit Rev Oncol Hematol 1995;21(1-3):1-18. 5. Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001;276(11):7806-10. 6. Ganz T. Hepicidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 2003;102(3):783-8. 7. Means RT Jr. Advances in anemia of chronic disease. Int J Hematol 1999;90:7-12. 8. Jurado RL. Iron, infections and anemia of inflammation. Clin Infect Dis 1997;25(4):888-95. 9. Siegel EH. Total erythrocyte, leucocyte and differential white cell counts of blood in chronic periodontal disease. J Dent Res 1945;24:270-71. 10. Hutter JW, Van der Velden U, Varoufaki A, Huffels RA, Hoek FJ, Loos BG. Lower numbers of hemoglobin in periodontitis patients compared to control subjects J Clin Periodontol 2001;28(10):930-6. Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

review article

Aspirin Resistance G Sengottuvelu*, K Babu Chakkravarthy

Abstract Aspirin is the cornerstone of therapy in atherothrombosis, encompassing a wide-spectrum of clinical entities. Evidence is growing to indicate that there are subpopulations that do not respond to antithrombotic action of aspirin. The term ‘aspirin resistance’ has been used to describe a number of different phenomena. Key words: Atherothrombosis, antiplatelet therapy

spirin is the cornerstone of therapy in atherothrombosis, encompassing a widespectrum of clinical entities. A meta-analysis of 287 clinical trials on aspirin in the prevention of cardiovascular disease has provided firm evidence that antiplatelet therapy, mainly aspirin, can reduce by approximately 25% the risk of nonfatal myocardial infarction (MI), nonfatal stroke or vascular death in high-risk patients, regardless of sex, age, presence of arterial hypertension or diabetes. An absolute reduction in the risk of having a serious vascular event was 36 per 1,000 MI survivors treated for two years. Undoubtedly, clinical benefits of aspirin are most apparent in patients with acute MI, which has been convincingly demonstrated in the landmark infarction trial, Second International Study of Infarct Survival (ISIS-2). Treatment failures occur with any drug and aspirin is no exception. Evidence is growing to indicate that there are subpopulations that do not respond to antithrombotic action of aspirin. The term ‘aspirin resistance’ has been used to describe a number of different phenomena, including inability of aspirin to:  Protect against cardiovascular events despite its regular intake *Senior Consultant and Interventional Cardiologist Dept. of Cardiology Apollo Hospitals, Chennai Address for correspondence Dr G Sengottuvelu Dept. of Cardiology Apollo Hospitals, Greams Lane Chennai - 600 006 E-mail: drgseng@gmail.com

Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012



To affect various laboratory tests, reflecting platelet activity.

Possible Causes of Recurrent Ischemic Vascular Events among Patients Taking Aspirin Nonatherothrombotic Causes of Vascular Events 



Embolism from the heart (red fibrin thrombi, vegetations, calcium, tumor, prostheses) Arteritis

Reduced Bioavailability of Aspirin   

Inadequate intake of aspirin (poor compliance) Inadequate dose of aspirin Concurrent intake of certain nonsteroidal antiinflammatory drugs (NSAIDs) (ibuprofen, indomethacin), possibly preventing the access of aspirin to cyclo-oxygenase-1 binding site.

Alternative Pathways of Platelet Activation 



Platelet activation by pathways that are not blocked by aspirin (for example, red cell-induced platelet activation: Stimulation of collagen, adenosine diphosphate, epinephrine and thrombin receptors on platelets). Increased platelet sensitivity to collagen and adenosine diphosphate. Biosynthesis of thromboxane by pathways that are not blocked by aspirin (for example, by cyclooxygenase-2 in monocytes and macrophages and vascular endothelial cells). 29

Review Article Increased Turnover of Platelets

Increased production of platelets by the bone marrow in response to stress (for example, after coronary artery bypass surgery), introducing into blood stream newly formed platelets unexposed to aspirin during the 24-hour dose interval (aspirin is given once-daily and has only a 20-minute half-life). Genetic Polymorphisms ď Ź

ď Ź

Polymorphisms involving platelet glycoprotein Ia/IIa, Ib/V/IX and IIb/IIIa receptors, and collagen and von Willebrand factor receptors. Polymorphisms of cyclo-oxygenase-1, cyclooxygenase-2, thromboxane A2-synthase or other arachidonate metabolism enzymes. Factor XIII Val 34 Leu polymorphism, leading to variable inhibition of factor XIII activation by low-dose aspirin.

How Common is Biochemical Aspirin Resistance? In studies investigating the prevalence of biochemical aspirin resistance, the range of prevalence estimates

for biochemical aspirin resistance varied from 5.5% to 56.8%, depending on the method of assessing platelet function, the definition of biochemical aspirin resistance, and the patients tested. These studies suggest that biochemical aspirin resistance is a measurable phenomenon in a substantial proportion of patients prescribed aspirin. However, the studies have several limitations, including small sample sizes, lack of agreement between different platelet function tests, different dose regimens and nonadherence, and little information about measurement stability over time (Table 1). Conclusions and Clinical Implications No current evidence shows that patients with biochemical aspirin resistance would respond better to alternative antiplatelet treatment regimens. Identifying such patients directly may be less cost-effective than prescribing aspirin to everyone at risk and accepting some treatment failures. We do not want to risk depriving some patients of a treatment that may benefit them, even though the effect may be small. Despite treatment failures, aspirin remains the single most cost-effective drug for the secondary prevention

Table 1. Laboratory Tests Used to Investigate Platelet Function

Test

Method

Advantages

Disadvantages

Platelet aggregation

Optical

Widely available Correlated with clinical events

Not specific Labor intensive Operator- and interpreter-dependent Assesses platelet function in the absence of erythrocytes and blood flow (shear stress)

Semi-automated PFA-100, verify now aspirin assay

Simple Rapid Correlated with clinical events Assesses platelet function in presence of erythrocytes and high shear

Moderately expensive Uncertain sensitivity and specificity Platelet membrane receptor expression

Platelet membrane receptor Expression

P-selectin flow cytometry

Expression indicates platelet activation

Uncertain sensitivity and specificity Uncertain reproducibility Uncertain correlation with clinical events Results highly dependent on flow models Expensive Labor intensive

Platelet-release products

Soluble P-selectin

Simple Correlated with clinical events Long-term storage

Uncertain sensitivity and specificity Uncertain reproducibility

Urinary thromboxane excretion

Simple Correlated with clinical events Long-term storage

Uncertain sensitivity and specificity Uncertain reproducibility

Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

Review Article of atherothrombotic disease. To optimize its clinical effectiveness, clinicians should be aware of the potential causes of aspirin treatment failure, prescribe aspirin in appropriate doses and encourage patients to take aspirin, stop smoking and avoid regular use of NSAIDs and add other antiplatelet drugs.

10. Valles J, Santos MT, Aznar J, Osa A, Lago P, Cosin J, et al. Erythrocyte promotion of platelet reactivity decreases the effectiveness of aspirin as an antithrombotic therapeutic modality: the effect of low-dose aspirin is less than optimal in patients with vascular disease due to prothrombotic effects of erythrocytes on platelet reactivity. Circulation 1998;97(4):350-5.

Suggested Reading

11. Karim S, Habib A, Lévy-Toledano S, Maclouf J. Cyclooxygenase-1 and -2 of endothelial cells utilize exogenous or endogenous arachidonic acid for transcellular production of thromboxane. J Biol Chem 1996;271(20):12042-8.

1. Antithrombotic Trialists Collaboration. Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86. 2. Second International Study of Infarct Survival (ISIS-2) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2:349-60. 3. Juul-Móller S, Edvardsson N, Jahnmatz B, Rosén A, Sørensen S, Omblus R. The Swedish Angina Pectorics Aspirin Trial (SAPAT) group. Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris. Lancet 1992;340:1421-5. 4. Tran H, Anand SS. Oral antiplatelet therapy in cerebrovascular disease, coronary artery disease, and peripheral arterial disease. JAMA 2004;292(15): 1867-74. 5. Evangelista V, Totani L, Rotondo S, Lorenzet‑R, Tognoni G, De Berardis, et al. Prevention of cardiovascular disease in type-2 diabetes: how to improve the clinical efficacy of aspirin? Thromb Haemost 2005;93(1):8-16. 6. De Gaetano G; Collaborative. Group of the Primary Prevention Project. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomized trial in general practice. Lancet 2001;357:89-95. 7. Sanmuganathan PS, Ghahramani P, Jackson PR, Wallis EJ, Ramsay LE. Aspirin for primary prevention of coronary heart disease: safety and absolute benefit related to coronary risk derived from meta-analysis of randomized trials. Heart 2001;85(3):265-71. 8. Patrono C, Bachmann F, Baigent C, Bode C, De Caterina R, Charbonnier B, et al.; European Society of Cardiology. Expert consensus document on the use of antiplatelet agents. The task force on the use of antiplatelet agents in patients with atherosclerotic cardiovascular disease of the European Society of Cardiology. Eur Heart J 2004;25(2):166-81. 9. Rocca B, Seccheiero P, Ciabattoni G, Ranelletti‑FO, Guitani L, Guidotti L, at al. Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets. Proc Natl Acad Sci USA 2002;99(11):7634-9. Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

12. Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara‑AJ, DeMarco S, Tournier B, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 2001;345(25):1809-17. 13. FitzGerald GA. Parsing an enigma: the pharmacodynamics of aspirin resistance. Lancet 2003; 361:542‑4. 14. Undas A, Brummel K, Musial J, Mann KG, Szczeklik‑A. Pl(A2) polymorphism of beta(3) integrins is associated with enhanced thrombin generation and impaired antithrombotic action of aspirin at the site of microvascular injury. Circulation 2001;104(22):2666-72. 15. Szczeklik A, Musial J, Undas A, Swadzba S, Góra PF, Piwowarska W, et al. Inhibition of thrombin generation by aspirin is blunted in hypercholesterolemia. Arterioscler Thromb Vasc Biol 1996;16(8):948-54. 16. Szczeklik A, Musial J, Undas A, Gajenski P, Góra P, Swadzba J, et al. Inhibition of thrombin generation by simvastatin andlack of additive effects of aspirin in patients with marked hypercholesterolemia. J Am Coll Cardiol 1999;33(5):1286-93. 17. Steering Committee of the Physicians_ Health Study Research Group. Final report on the aspirin component of the ongoing Physicians_Health Study. New Engl J Med 1989;321(3):129-35. 18. Meade TW, Brennan PJ. Determination of who may derive most benefit from aspirin in primary prevention: subgroup results from a randomized controlled trial. BMJ 2000;321:13-7. 19. Kawasaki T, Ozeki Y, Igawa T, Kambayashi J. Increased platelet sensitivity to collagen in individuals resistant to low-dose aspirin. Stroke 2000;31(3):591-5. 20. Kunicki TJ. The influence of platelet collagen receptor polymorphisms in hemostasis and thrombotic disease. Arterioscler Thromb Vasc Biol 2002;22(1):14-20. 21. Mustonen P, van Willigen G, Lassila R. Epinephrine‑ viaactivation of p38-MAPK - abolishes the effect of aspirin on platelet deposition to collagen. Thromb Res 2001;104(6):439-49.

clinical study

Clinical Outcome in Malaria - Reiterating the Role of Parasitic Index Aarthi Rajkumar*, Shalinee Rao**, Sandhya Sundaramâ&#x20AC;

Abstract Malaria is a common parasitic infection seen in the tropics. The most common clinical presentation of malaria is fever with chills and rigors. However, it can also manifest with systemic complications depending on the immune status of the individual and degree of parasitemia. This study was undertaken to look at the various clinical patterns of presentation of malaria and the impact of parasitemia on disease progression and recovery. Parasitic index (PI) was calculated and graded and was found to correlate with the severity of disease. Key words: Complications, malaria, parasitic index

alaria is a major health hazard in India and other tropical countries. Approximately 300 million people worldwide are inflicted with malaria and each year, between 1-1.5 million die due to malaria.1,2 Though malaria presents as an uncomplicated fever with prompt recovery, it may mimic many systemic illness confounding the treating physician in individuals with low immunity. The classic triad of fever with chills and rigors is often masked by other symptoms like jaundice, renal failure, acidosis, hypoglycemia and electrolyte imbalance. Many patients with malaria present with systemic complications, especially renal and hepatic failure.3 The present study was undertaken to analyze the various clinical presentation of malaria with their hematological and biochemical parameters and to correlate the severity and outcome of the disease with the parasitic index (PI).

which were diagnosed as malaria, on Leishman stained thin smears and confirmed by quantitative buffy coat (QBC) analysis were included in the study. PI was estimated by counting the number of parasitized red blood cells (RBCs) among 1000 RBCs. Only asexual forms (ring, trophozoite and schizont) were included for calculating the PI. The parasitic load was graded on a scale of I-IV corresponding to 0-5%, 6-10%, 11-20% and >20%, respectively. Hematological parameters like hemoglobin, white blood cell count, platelet count, reticulocyte count, prothrombin time (PT), partial thromboplastin time (PTT) and biochemical parameters like blood urea nitrogen (BUN), creatinine, bilirubin, glucose and electrolytes were also noted from the clinical case sheets archived from the medical record department.

material and methods

Forty-six cases were identified as malaria-positive in this period. Plasmodium vivax was found to be the commonest form of infection followed by falciparum. Mixed infections with falciparum and vivax were also seen (Fig. 1).

This was a retrospective study done in the post monsoon period between October 2006 and March 2007. Cases, *Assistant Professor **Associate Professor â&#x20AC; Professor Dept. of Pathology Sri Ramachandra Medical College and Research Institute, Porur, Chennai Address for correspondence Dr Aarthi Rajkumar Assistant Professor Dept. of Pathology Sri Ramachandra Medical College and Research Institute Porur, Chennai - 600 116 E-mail: aarthirajkumar96@gmail.com

RESULTS

Fever was the most common presenting symptom observed in 96% of cases (Table 1). Thrombocytopenia was the commonest lab hematological abnormality seen in 48% of cases. Hyperbilirubinemia, electrolyte imbalance, raised BUN/creatinine was also noted (Fig. 2). Systemic complications were seen in only 27 cases (Table 2). Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

CLINICAL STUDY

Vivax Falciparum Mixed

5 5

22 7

Figure 2. Laboratory abnormalities

Figure 1. Species specific case distribution.

Table 1. Signs and Symptoms Symptoms

Thrombocytopenia Hemoglobin <5 gm% Reticulocyte BUN/Creatinine Electrolyte imbalance Bilirubin

Number and percentage of cases

PI was <10% in 89% of cases and these patients had a good outcome and recovered, while five patients (11%) succumbed to the infection. All the five patients who died, developed disseminated intravascular coagulation (DIC) and had a PI >10% (Table 3).

Fever

44 (96%)

Chills

20 (43%)

DISCUSSION

Vomiting

7 (16%)

â&#x2020;&#x201C;Urine output

7 (16%)

Headache

5 (11%)

Dark urine

5 (11%)

Diarrhea

5 (11%)

Altered sensorium

5 (11%)

Malarial parasite is a protozoa belonging to genus Plasmodium with four species, namely vivax, ovale, malariae and falciparum that are pathogenic to man. Of these, P. vivax malaria is prevalent in many regions of the world and accounts for more than half of all malaria cases in Asia and Latin America.4 A study done by Koh et al showed that P. vivax accounted for upto 50% of malaria cases in South-East Asian population.5 In our study too, the commonest species causing malaria was P. vivax, (58%), followed by falciparum (35%) and mixed infection with falciparum and vivax infection (7%).

Stupor/Unconsciousness

Table 2. Complications Complication

Falciparum

Vivax

Total

Acute renal failure

Cerebral malaria

Jaundice

DIC

ARDS/Sepsis

The clinical manifestation of malaria is variable ranging from fever with chills and rigors to vomiting, malaise, headache and myalgia. These symptoms are nonspecific and cannot be distinguished reliably from other febrile illnesses.6 Some patients can also present with symptoms resulting from complications such as renal failure, coma, diarrhea, jaundice and severe

Table 3. Parasitic Index and Clinical Outcome Parasitic index

Falciparum

Vivax

Mixed

Total

0-5%

6-10%

11-20%

>20%

Complication

Outcome

Nil

Recovered

IVH and ARF

Recovered

DIC, IVH, ARF Electrolyte imbalance

Expired

DIC, ARF, ARDS

Expired

IVH = Intravascular hemolysis; ARF = Acute renal failure; DIC = Disseminated intravascular coagulation; ARDS = Acute respiratory distress syndrome.

Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

CLINICAL STUDY anemia. Recently, there has been a change in the trend of clinical manifestations of malaria, with more and more patients presenting to tertiary care hospitals.3,5 High fever is the commonest clinical presentation in any species of malaria, a finding which was also noted in our study. Fever with chills and rigors is seen more often in vivax infection than falciparum and this is thought to coincide with the period of schizont rupture.6 Surprisingly, we found fever with chills and rigors in only 48% of our cases and these were mostly seen in vivax infection. Many systemic complications are seen in malaria such as renal failure, jaundice, cerebral malaria, acute respiratory distress syndrome (ARDS) and DIC. Renal involvement in malaria varies widely from asymptomatic proteinuria to acute renal failure (ARF). Dehydration and increased catabolism has been attributed to development of renal derangement in malaria patients. Mild renal dysfunction in the form of albuminuria is seen in 20-90% of patients in Plasmodium falciparum malaria but only a few of these progresses to renal failure. The development of renal failure and mortality in these patients is influenced by the parasitic load.7 Our study also demonstrated that a high PI leads to the development of ARF and was a poor prognostic factor as five of the seven cases that developed ARF expired and all of them had severe parasitemia (>10%). Hepatic dysfunction can also be seen in malaria. Jaundice is believed to occur as a result of intravascular hemolysis of parasitized erythrocytes, hepatic dysfunction and possibly due to microangiopathic hemolysis associated with DIC.2 Hemolysis usually causes an unconjugated hyperbilirubinemia, while hepatic dysfunction produces conjugated bilirubinemia. The incidence of jaundice in malaria ranges from 20 to 31% and it is predominantly hemolytic with a high parasitic load.3 In our study, all five cases of jaundice had a high PI though intravascular hemolysis was noted in only two of these. Cerebral malaria is observed more frequently in falciparum than vivax. The pathogenic mechanism in cerebral malaria involves sequestration of parasitized RBCs in microvasculature of brain due to cytoadherence, rosette formation and decreased deformability of infected erythrocytes. This causes hypoxia and release of cytokine tumor necrosis factor-Î˛ (TNF-Î˛), which in turn upregulates nitric oxide synthetase activity 34

interfering with calcium influx thereby producing coma.3 In our study, five patients were diagnosed with cerebral malaria as per WHO criteria. Although, the parasitic load was high in these patients all of them recovered after treatment with intravenous quinine as there were no associated systemic complications. Thrombocytopenia is the commonest hematological derangement noted in patients with malaria. In our study too, it was observed in 22 cases. Sequestration of platelets in the spleen or their consumption as in DIC are thought to be important causes of thrombocytopenia in malaria.2 Anemia is also a common feature of acute malarial infection. It may develop rapidly in falciparum infection due to heavy parasitemia and destruction of parasitized RBCs.3 Severe anemia with a hemoglobin concentration <5 gm% was seen in only two cases in our study. Malaria is an important cause of multiple organ failure in India. Mortality rate is 6.4% when one organ fails but increases to 48.8% with failure of â&#x2030;Ľ2 organs.8 Hyperparasitemia is believed to be an important cause of multiorgan failure and death in malaria.3,5,9 In our study, the mortality rate due to malaria was 10.8%. Thirty-nine cases with low parasitemia had no complications and complete recovery. Two cases with ARF and low PI recovered, while five cases with severe parasitemia developed multiorgan failure with DIC and expired. This highlights the fact that parasitic load remarkably influences clinical outcome. The incidence of mixed infection with vivax and falciparum is reported to be <2%. Concurrent infections with different Plasmodium species may have important role in the development of cross-species immunity and a milder clinical course. Mixed infections with vivax appear to reduce the severity of disease with falciparum, decreasing the risk of complications and treatment failure.4 This was also evident in our study as all cases of mixed infection had a low parasitemia and showed prompt recovery. Complications and fatality are more common with falciparum than vivax infection.9,10 In our study, of the five who expired, only one died due to vivax infection. Systemic complications like renal failure, hepatic dysfunction, ARDS and DIC occurred with falciparum infection showing that it was more fulminant than vivax. Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

CLINICAL STUDY Cases without any complication responded well to antimalarials regardless of the causative species. In this study, PI correlated well with the severity and course of disease. Complications and mortality was seen more often in patients with a higher degree of parasitemia. Hence, knowledge of PI could be a valuable tool for predicting clinical outcome and planning appropriate therapy. References 1. Muddaiah M, Prakash PS. A study of clinical profile of malaria in a tertiary referral centre in South Canara. J Vector Borne Dis 2006;43(1):29-33. 2. Banzal S, Ayoola EA, El Sammani EE, Gadour MO, Jain AK. The clinical pattern and complications of severe malaria in the Gizan region of Saudi Arabia. Ann Saudi Med 1999;19(4):378-80. 3. Nand N, Aggarwal H, Sharma M, Singh M. Systemic manifestations of malaria. J Indian Acad Clin Med 2001;2(3):189-94. 4. Price RN, Tjitra E, Guerra CA, Yeung S, White NJ, Anstey NM. Vivax malaria: neglected and not benign. Am J Trop Med Hyg 2007;77(6 Suppl):79-87.

5. Koh KH, Chew PH, Kiyu A. A retrospective study of malaria infections in an intensive care unit of a general hospital in Malaysia. Singapore Med J 2004;45(1):28-36. 6. Mandell, Douglas, and Bennnet. Principles and Practice of Infectious Diseases. 6th edition, Churchill Living Stone Publication; 2005. 7. Trang TT, Phu NH, Vinh H, Hien TT, Cuong BM, Chau TT, et al. Acute renal failure in patients with severe falciparum malaria. Clin Infect Dis 1992;15(5): 874-80. 8. Krishnan A, Karnad DR. Severe falciparum malaria: an important cause of multiple organ failure in Indian intensive care unit patients. Crit Care Med 2003; 31(9):2278-84. 9. Kochar DK, Saxena V, Singh N, Kochar SK, Kumar SV, Das A. Plasmodium vivax malaria. Emerg Infect Dis 2005;11(1):132-4. 10. Sitalakshmi S, Srikrishna A, Devi S, Damodar P, Mathew T, Varghese J. Changing trends in malariaa decadeâ&#x20AC;&#x2122;s experience at a referral hospital. Indian J Pathol Microbiol 2003;46(3):399-401.

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case report

Epidermal Nevus Syndrome with Hemihypertrophy of the Body Jayakar Thomas*, Manoharan R*, Sindhu Ragavi B*, Prakash K**

Abstract This is an interesting case report of a 14-year-old girl presenting with epidermal nevus over the face, neck and back with right sided hemihypertrophy and hemimegalencephaly. Key words: Epidermal nevus syndrome, hemihypertrophy of the body, hemimegalencephaly

pidermal nevi (EN) are congenital hamartomas originating from the embryonal ectoderm. They arise from pluripotent germinative cells of the basal layer of the embryonic epidermis. They are classified on the basis of their main components, which may be keratinocytic, sebaceous, apocrine, eccrine, or follicular. Around one-third of patients with epidermal nevi have involvement of other organ systems, called as the epidermal nevus syndrome (ENS). It is also termed as Solomon syndrome. Schimmelpenning first described epidermal nevi with neurologic anomalies; hence, it is also known as Schimmelpenning syndrome.1 Case Report

Figure 1. Epidermal nevus with hemihypertrophy of face.

A 14-year-old female born of non consanguineous marriage came to our outpatient department with complaints of pigmentation and rough skin on right side of face extending to the neck along with thickened lips on the right side since birth. There was a history of expansion of the lesion as the child grows. There was also a history of learning difficulty, but otherwise her growth and development were normal. There was no history of seizure disorder, altered vision or hearing difficulty. The girl had undergone a surgery for cleft lip on the right side two years back.

On examination, a well-defined pigmented verrucous plaque extending from the face to the upper chest

Figure 2. Epidermal nevus seen as a verrucous plaque involving the right side of neck.

*Dept. of Dermatology **Dept. of Radiology Sree Balaji Medical College and Hospital, Bharath University, Chennai Address for correspondence Dr Jayakar Thomas Dept. of Dermatology Sree Balaji Medical College and Hospital Bharath University, Chennai - 600 044

anteriorly. The plaque was seen to cover the entire right side of face and neck extending from the forehead to 2 cm below the clavicle. Associated hypertrichosis was present. A similar plaque of approximately 2 Ă&#x2014; 3 cm size with hypertrichosis was seen over the center of upper back (Figs. 1, 2 and 3). Unilateral macrochelia was Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

Case Report

Figure 3. Epidermal nevus seen over the back.

Figure 6. HPE of lesional skin taken from right upper lip showing increased blood vessels and lymph spaces.

Figure 4. Hemihypertrophy of the right hand.

Figure 7. T2 image of MRI (coronal section) showing right cerebral and cerebellar hemisphere enlargement.

Figure 5. HPE of skin lesion taken from right temple showing hyperplastic epidermis with mild acanthosis and prominent hair follicles and sebaceous glands in the dermis

present on the right side. Hemihypertrophy was noted on the right side of the body involving the face (Fig. 1) neck, trunk, upper (Fig. 4) and lower limbs. Oral mucosa showed right buccal hypertrophy with diffuse pigmentation. Histopathology of the lesion from Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

Figure 8. T1 image of MRI (sagittal section) showing bilateral symmetrical T1 hyperintensity noted involving bilateral gangliocapsular region and cerebral peduncles.

the right temple showed hyperplastic epidermis with mild acanthosis and uniform basal zone pigmentation (Fig. 5). In the dermis, prominent hair follicles and sebaceous glands were seen. Another section taken from the swelling over the lip showed increased blood vessels and lymph spaces (Fig. 6). USG of both upper and lower limbs showed subcutaneous tissue and muscle hypertrophy including upper and lower limbs. MRI of brain showed right sided hemimegalencephaly involving the cerebrum and cerebellum (Figs. 7 and 8). Intelligence quotient (IQ) testing done revealed a low score of 67, which correlates clinically to mild mental retardation. With all these constellation of findings, we came to a conclusion of epidermal nevus syndrome with hemihypertrophy and hemimegalencephaly. 37

Case Report Discussion Epidermal nevus syndrome is a rare congenital hamartoma arising from the embryonal ectoderm. The age of onset ranges from birth to 40 years. Epidermal nevi present as patches, plaques, or nodules that may be bilateral or distributed on most of the body. In our case, it was a 14-year-old girl, whose skin lesions were present from birth. She presented with verrucous plaques associated with hypertrichosis over the right side of face and neck. Epidermal nevus presenting with neurological abnormalities is also called as Schimmelpenning syndrome. Our patient had neurological abnormalities like hemimegalencephaly and low IQ. Epidermal nevus is also known to be associated with skeletal abnormalities and hemihypertrophy involving any part of the body, which was also noted in our patient. Sakuta et al have described a patient of epidermal nevus syndrome with hemimegalencephaly and hemihypertrophy of the body.2 Allison et al have described a variant of epidermal nevus syndrome with hemimegalencephaly, facial hemihypertrophy and gyral malformation.3 In our patient, hemihypertrophy was seen involving the whole right half of the body. Marinoni et al have reported a patient with epidermal nevus since birth with hemihypertrophy of the face who started developing seizures later in life, thus stressing the importance of epidermal nevus syndrome as an early marker of syndromes involving central nervous system.4 Neumann et al have described cerebral manifestations, hemihypertrophy and lymphedema of one leg in a child with epidermal nevus syndrome. In this boy,

despite evident brain pathology in MRI, he lacked neurological symptoms and mental retardation, similar to our case.5 Conclusion Epidermal nevus syndrome can present in different forms with or without neurological abnormalities when first seen. However, these patients have to be followed up carefully for their entire life time as they may develop neurological morbidities even later in life. References 1. Happle R. Gustav Schimmelpenning and the syndrome bearing his name. Dermatology 2004;209(2):84-7. 2. Sakuta R, Aikawa H, Takashima S, Yoza A, Ryo S. Epidermal nevus syndrome with hemimegalencephaly: a clinical report of a case with acanthosis nigricanslike nevi on the face and neck, hemimegalencephaly, and hemihypertrophy of the body. Brain Dev 1989;11(3):191-4. 3. Allison MA, Dunn CL, Pedersen RC. What syndrome is this? Epidermal nevus syndrome: a neurologic variant with hemimegalencephaly, facial hemihypertrophy and gyral malformation. Pediatr Dermatol 1998;15(1): 59-61. 4. Marinoni LP, Giraldi S, Taniguchi K, Carvalho VO, Bertogna J, Antoniuk S, et al. Epidermal nevus syndrome - a case report. J Pediatr (Rio J) 1999;75(4):287-90. 5. Neumann LM, Scheer I, Kunze J, Stรถver B. Cerebral manifestations, hemihypertrophy and lymphoedema of one leg in a child with epidermal nevus syndrome (Schimmelpenning-Feuerstein-Mims). Pediatr Radiol 2003;33(9):637-40.

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case report

Fibrothecoma of Ovary with Torsion: A Rare Case of Ovarian Tumor T Shoba*, BO Parijathim**, Hemalatha†, Shanthi†, Vindu‡

Abstract In this article, we report a case of 45-year-old lady who presented with acute abdomen. A diagnosis of torsion of right ovarian cyst was made on grounds of preoperative investigation and surgery was planned. Histopathological examination revealed a fibrothecoma of the ovary with torsion. Key words: Benign tumor, fibrothecoma, ovary, torsion

varian fibrothecoma is a sex cord stromal tumor, which accounts for 5% of all ovarion tumors. It usually occurs in patients over 40 years of age. The difference between thecoma and fibroma is occasionally imprecise because of histologic and immunohistochemical overlap between them. Therefore, the term fibrothecoma has been frequently used. Ovarian fibrothecoma usually presents as unilateral, solid well capsulated, hard mass with bosselated external surface. Our case showed on cut surface organised blood along with grey white and homogenous with a whorled pattern with interlacing bundles of fibrous tissue. Ovarian fibrothecoma is almost always benign in nature. Surgical resection is the preferred treatment and is generally associated with a good prognosis. It may be associated with ascites and hydrothorax known as Meigs syndrome. We report a case of ovarian fibrothecoma with torsion for its rarity. Case Report A 45-year-old female presented to the Dept. of obstetrics and gynecology department with complaints of pain and abdominal discomfort for two years. Her *PG Student **Professor and Head † Professor ‡ Associate Professor Dept. of Pathology, SBMCH, Bharath University, Chennai Address for correspondence Dr T Shoba 7, Works Road, New Colony Chrompet, Chennai - 600 044 E-mail: spkshobakishore@yahoo.com Source: Nil, Conflict of Interest: None declared

Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

general physical examination was unremarkable. Per abdominal examination was also normal. Per vaginal examination revealed a soft mobile mass around 12 × 7 cm in size on right side. Other fornices were free. Routine laboratory tests were within normal limits. Pre operative CA-125 level was normal. An abdominal ultrasonography was suggestive of right ovarian cyst. Uterus and left ovary were normal. Based on clinical presentation and investigations, a provisional clinical diagnosis of torsion of right ovarian cyst was considered. Patient was planned for elective laparotomy. She developed acute pain abdomen two days prior to elective surgery. The patient was taken up for emergency laparotomy on that day itself and underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy (BSO). Right ovarian cyst of 12 × 8 cm, hemorrhagic was found. Other tube and ovary, uterus were normal. An exploration of the abdominal cavity revealed ascitic fluid around 200 ml. The abdomen was closed after peritoneal toileting. The entire specimen was sent for histopathological examination. Pathological Findings

Fig. 1 shows Grossly, the uterus with cervix measuring 8 × 6 × 2 cm. Right ovarian mass along with fallopian tube measuring 12 × 8 × 2 cm. External surface congested bossellated. Cut surface shows solid, firm, greyish white areas with areas of hemorrhage and presence of organised blood clot. Grossly there was no necrosis. Tube appeared congested. Left ovary measuring 2 × 1 cm, cut surface tiny cysts seen. Uterus unremarkable. 39

Case Report ovary shows ovarian parenchyma with cystic follicles. Sections from utreus and both tubes were unremarkable. Sections from cervix shows chronic cervicitis. Ascitic fluid for cytology examination was negative for malignant cells. Disscussion Figure 1. Gross photography of the specimen shows uterus with cervix and cross section of ovarian mass showing solid areas with hemorrhage.

Figure 2. Low power 10X photomicrography showing spindle cells in fasicles and foci of storiform pattern.

Ovarian fibrothecomas are uncommon tumors of gonadal stromal cell origin and account for 5% of all ovarian tumors. They are rarely malignant and 90% of casess are unilateral. Torsion is not an uncommon presentation occuring in 8% of the patients. The tumor is composed of spindle, oval or round to polyhedral shaped cells with clear cytoplasm. Fibrothecomas are usually solid, spherical, slightly lobulatrd and encapsulated congested greyish-white masses covered by a glistening, intact ovarian serosa. They are almost always benign. Surgical removal is recommended. Tumorectomy is indicated for young patients. In peri and postmenopausal women TAH with BSO is indicated because of the low probability of malignancy. Samanth, et al have also reported benign ovarian stromal tumor associated with free peritoneal fluid as in our case. In our case, surgery was planned for right ovarian cyst which underwent torsion, histopathologically diagnosed as fibrothecoma with torsion. Surgery proved to be curative with an uneventful post operative course. Conclusion

Figure 3. High power (40X) photomicrography shows spindle cells with benign nuclei and oval or round to polyhedral shape cells with clear cytoplasm.

Microscopically, right ovary Fig. 2 low power 10x shows lesion composed of spindle shaped cells are arranged in sheets and fasciles. Foci shows storiform pattern. Fig. 3 high power 40x shows neoplasm composed of spindle shaped cells with benign nuclei arranged in interlacing bundles of fasciles admixed with oval or round to polyhedral with moderate to abundant pale or vaculated cytoplasm in a background of fibrocollagenous stroma. Areas of hemorrhage and congested capillaries are also seen. There is no necrosis. No abnormal mitotic figures seen. Sections from left 40

The present case report emphasizes the rare presentation and unique gross morphology of ovarian fibrothecoma. Histopathological examination is essential to confirm the diagnosis of fibrothecoma from other solid ovarian mass. Suggested Reading 1. Samanth kk, Black wc III. Benign ovarian stromal tumors associated with free peritoneal fluid. Am S obstel Gynecol 1970;107:538-45. 2. Young RH, Sully RE. Ovarian sex-cord stromal tumor. problems in differiential diagnosis. Pathol Anne 1988;23(pt 1):273-96. 3. Outwater EK, Wagner BJ, MannionC, MCKarney JK, Kim B, Sexcord stromal and steroid cell tuomr of the ovary. Radiographics 1998;18:1523-46. Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

case report

Idiopathic Sclerosing Encapsulating Peritonitis Presenting As Spontaneous Multiple Jejunocolic Fistula KP Arun*, P Sashikumar*, Bhanumathi*, Neha Prashant Shah*, Kabongo*

Abstract Idiopathic Sclerosing encapsulating peritonitis (SEP) is a rare cause of spontaneous enterocolic fistula ,that is characterized by a thick greyish-white fibrotic membrane encapsulating the peritoneal cavity. ISEP can be classified as idiopathic, also known as abdominal cocoon and secondary. Diagnosis are usually incidental at laparotomy, surgery is the main management of ISEP. Key words: Sclerosing encapsulating peritonitis, idiopathic abdominal cocoon, enterocolic fistula

ejunocolic fistula, a very rare internal fistula, usually occurs in a background of malignancy1,2 or diverticular3 diseases. Here we present a case report of a patient who had a spontaneous double fistula of unknown origin, associated with abdominal cocoon, successfully managed by laparotomy and resection of the fistula with bowel resection and anastomosis. Case Report A 38-year-old gentleman presented with progressive weight loss over a period of six months, watery stools of 15-20 times per day, passage of undigested food in stools shortly after eating, recurrent bouts of fever, progressive fatigue and weakness. On examination, he had signs of malnutrition like decreased turgor of skin, thinned nail, anemia and mild bipedal edema. There were no palpable lumps or scars on the abdomen and no obvious fistula could be made out. Rectal examination was normal. No evidence of tuberculosis4 or malignancy was revealed in general examination. Hypoproteinema and anemia were found in the complete blood picture. Ultrasound scan of the abdomen showed no obvious abnormality but colonoscopy (TB) revealed two large fistulous stoma-like opening close to the splenic flexure, along the transverse colon (Fig. 1). *Consultant Senior Surgeon Dept. of Surgical Gastroenterology Life Line Multispeciality Hospital, Chennai Address for correspondence Dr JS Rajkumar Dept. of Surgical Gastroenterology Lifeline Group of Hospital 5/639, Rajiv Gandhi Salai (OMR) Perungudi Chennai - 600 096 E-mail: arunkperiasamy@gmail.com

Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

Contrast-enhanced computerized tomography (CT) was performed with the contrast administered intra rectally. This showed rapid entry of contrast from the transverse colon into the proximal loops of the jejunum (Fig. 2). Diagnosis of spontaneous jejunocolic fistula5 was made after radiological investigations. In view of the patientâ&#x20AC;&#x2122;s progressive weakness, loss of weight and intra-abdominal jejunocolic fistulae, we decided to take him up for a diagnostic laparoscopy to attempt disconnection of the fistula. He underwent preoperative work up and optimization with high protein diet, fresh frozen plasma, albumin and blood. Laparoscopy revealed a thick dense cocoon with no further entry being possible even after three ports were inserted using the open and optical trochar techniques. But as there was still no visibility due to dense cocoon, we proceeded to do a laparotomy. Laparatomy revealed intra-abdominal cocoon6 involving the complete small bowel and the visible large bowel. It was dense in the parietal area and filmsy in between the bowels. There was no obvious evidence of intra-abdominal TB or malignancy. The picture looked like one of idiopathic sclerosing encapsulating peritonitis, a rare condition marked by diffused intraabdominal cocoon with fibrous, vascular and avascular adhesions between the various parts of the bowel and between bowel and the anterior abdominal wall (Fig. 3). The entire small bowel and the large bowel were slowly and carefully dissected off from all the adhesions to reveal two large jejunocolic fistulae (Fig. 4) occurring at 25 cms from the duodeno jejunal (DJ) flexure and 45 cms from the DJ flexure and fistulating into the distal transverse colon close to the 41

Case Report

Figure 1. Colonoscopy showing fistulous opening in transverse colon.

Figure 3. Bowel adhesion due to ISEP on laparotomy.

Figure 2. Abdominal CT reveals fistula between transverse colon and jejunum.

Figure 4. Jejunocolic fistula on laparotomy.

splenic flexure to the midtransverse colon respectively. After complete entero and cololysis were performed, both the fistulous tracts going from the jejunum to the colon were disconnected using a stapler across the tract close to the colon. The area between 25 cm and 45 cm from the DJ flexure along the jejunum was also diseased with multiple jejunojejunal fistulation and adhesions and therefore this 20 cms of bowel was also resected and anastomosed using a double stapler technique. All the resections and anastomosis were performed by using Ethicon 55 mm and 75 mm blue (3.5 mm) cartridge staplers of the linear cutter type.

period was uneventful and the patient made a good recovery. Histopathology of the excised bowel revealed proliferation of fibroconnective tissue with non specific chronic inflammatory reaction.

In order to support the bowel in case of leak, a feeding jejunostomy was also inserted. Post operative 42

Discussion Idiopathic sclerosing encapsulating peritonitis (ISEP)7 is a condition in which a capsule-like cocoon forms all around the small bowel. The usual presentation of ISEP is small bowel obstruction but in our case it is one of a spontaneous jejunocolic fistula. It is postulated that farmers exposed to particular types of rye and barley might develop this complication in the peritoneum, as could young girls who have peritoneal entry of bacteria through their fallopian tubes. The etiology Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

Case Report not withstanding, it is well-known that the dense cocoon involves the small bowel and the large bowel in multiple fibrous adhesions. As part of the ongoing inflammatory process, bowel-to-bowel fistulae or small bowel-to-colon fistulae may also develop. It probably did in our patient. As there has been no evidence of tuberculosis, Crohn’s disease8,9,10 or any other specific inflammatory pathology in the dissected specimens, we did not proceed with any specific treatments either. Many drugs have been used for idiopathic encapsulating peritonitis, one of them is b-blocker, which is supposed to decrease the fibrosis in the retro peritoneal plane, the other being steroids. In this case as the patient was quite comfortable, we decided not to proceed with any further chemical therapy and to merely follow up the patient. If this patient had histological evidence of Crohn’s disease, he would have been a good candidate for infliximab as there is definite data that infliximab11 prevents multiple fistulae in patients with Crohn’s or ulcerative colitis. Fortunately, he had no evidence any of these conditions. The other causes of jejunocolic fistula are malignancy in the jejunum or in the colon that perforates to the adjoining bowel and causes a continuous fistula, diverticular disease of the jejunum or diverticular disease of the colon penetrating transmurally causing a fistula and GIST tumors12 of the small or large bowel. Apart from these, there have been case reports of jejunocoloic fistula in patients with radiation13 enteropathy and colopathy. It is significant to mention here that our patient suffered from ISEP, which is the most likely cause of fistulae. Long-term, methysergide us may also precipitate bowel or bladder obstruction along with a retroperitoneal fibrosis-like picture, but such history was not forthcoming either. In the absence of all other specific diseases and with the above said histopathology, it is most likely that this patient is indeed suffering from ISEP. The small and the large bowels were released and the fistula were both adequately disconnected. The patient is now well on follow up 15 days post surgery and we are adopting a “wait and watch” policy to see if he requires

any further antifibrotic medication for his rare intra peritoneal condition. Reference 1. Gasparini G, Marini U. On a case of gastrocolic and jejunocolic fistulas caused by neoplasm of the transverse colon. Ann Radiol Diagn (Bologna) 1960;33:363-74. 2. Lin JS, Fan HA, Wang TC, Lin CH. Jejunocolic fistula due to reticulum cell sarcoma of the jejunum. Kumamoto Igakkai Zasshi 1970;44(1):78-80. 3. Williams C, Bosher LH Jr. Jejunal diverticulosis complicated by the development of jejuno-colic and jejuno-jejunal fistulas; report of a case. Trans South Surg Assoc 1947-1948;59(1 vol.):167-73. 4. Tonouchi H, Miki C, Kusunoki M. A case of jejunocolic fistula suspected to be due to intestinal tuberculosis. J Abdominal Emergency Med 2001;4:747-50. 5. Abcarian H, Udezue N. Coloenteric fistulas. Dis Colon Rectum 1978;21(4):281-6. 6. Reynders D, Van der Stighelen Y. The abdominal cocoon. A case report. Acta Chir Belg 2009;109(6):772-4. 7. Xu P, Chen LH, Li YM. Idiopathic sclerosing encapsulating peritonitis (or abdominal cocoon): a report of 5 cases. World J Gastroenterol 2007;13(26):3649-51. 8. Marion JF, Lachman P, Greenstein AJ, Sachar DB. Rarity of fistulas in Crohn’s disease of the jejunum. 1995;1:34-6. 9. El-Hajj II, Abdul-Baki H, El-Zahabi LM, Barada KA. Primary coloduodenal fistula in Crohn’s disease. Dig Dis Sci 2007;52(1):59-63. 10. Nakae Y, Nagasako K, Sasaki H, Aoki G, Tanaka M. A case of Crohn’s colitis with gastrocolic and enterocolic and enterocolic fistulas (author’s transl). Nihon Shokakibyo Gakkai Zasshi 1975;72(7):865-70. 11. Sood A, Midha V, Sood N. Closure of jejuno-colic fistula in Crohn’s disease with infliximab. Indian J Gastroenterol 2001;20(4):164-5. 12. Shamsaeefar A, Hosseini SM, Motazedian N, Razmi T. Enterocolic fistula associated with a gastrointestinal stromal tumor. Indian J Cancer 2009;46(3):246-7. 13. Bushby CK, Snooks SJ, Shand WS. Jejunocolic fistula after radiation for malignant teratoma. J R Soc Med 1989;82(1):54-5.

Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

case report

Bilateral Ovarian Fibromatosis with Ascites Leena Dennis Joseph*, M Susruthan**, Jayanthi Mohan†, Tamizharasi‡, Sarah Kuruvilla¥

Abstract Ovarian fibromatosis is a very rare non neoplastic disease, which may clinically mimic a malignancy. This lesion presents as a tumor-like enlargement of one or both ovaries due to a non neoplastic proliferation of collagen-producing stroma. This case of bilateral ovarian fibromatosis in a 35-year-old female, is documented for its rarity of the lesion and the high index of suspicion for malignancy. Key words: Bilateral ovarian fibromatosis, mimic, tumor-like enlargement

umor-like ovarian enlargement due to a diffuse ovarian fibrosis is referred to as ovarian fibromatosis. It is a benign disorder that differs from other pelvic lesions with fibrosis, which include desmoid tumors, ovarian fibroma, Brenner’s tumor and Krukenberg’s tumor. This lesion poses a diagnostic problem as it can mimic a malignancy both clinically and radiologically. Clinical Details

A 35-year-old lady presented with pain lower abdomen for the past three days, which was dull aching in nature and aggravated on palpation. She gave a history of amenorrhea for the past two months, with weight gain and mild abdominal distension for the past one week. She underwent treatment elsewhere with antibiotics and an aspiration was done from the pouch of Douglas. The cytology smears were reported as malignancy possibly a serous cystadenocarcinoma of the ovary. There was pain on palpation over the lower abdomen, cervix appeared healthy and uterus was anteverted. There was fullness in both the fornices and a hard palpable mass was felt. Ultrasonography (USG) revealed both ovaries to be enlarged with multiple *Associate Professor (Pathology) **Assistant Professor (Pathology) † Professor of Obstetrics and Gynecology ‡ Assistant Professor in Obstetrics and Gynecology ¥ Professor of Pathology Sri Ramachandra University, Chennai Address for correspondence Dr Leena D Joseph Associate Professor (Pathology) Sri Ramachandra University, Chennai E-mail: leenadj@rediffmail.com

Figure 1. Ultrasonogram showing both ovaries to be enlarged with multiple small cysts with free fluid in the pouch of Douglas.

small cysts with free fluid in the pouch of Douglas (Fig. 1). Ovarian colour Doppler study showed no vascularity in the cyst wall or septations, suggestive of benignity. Ultrasonogram showed both kidneys to be normal in size and echotexture. A hysterectomy with bilateral salpingo-oophorectomy was done and the specimen was sent for histopathological examination. One ovary measured 8 cms and another one measured 5 cms in size. Externally, both the ovaries were nodular with focal hemorrhagic areas. Cut surface was solid grey white with tiny cystic spaces. Histopathology showed an increase in stromal cellularity (Fig. 2), with multiple tiny ovarian follicles trapped between the stroma (Fig. 3). There were few follicular cysts with focal areas of edema and collagenization in the ovarian stroma. A final diagnosis of ovarian fibromatosis was given. Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

Case Report

Figure 2. Sections showing increase in stromal cellularity (H&E X200).

Figure 3. Sections showing multiple tiny ovarian follicles trapped between the stroma (H&EX100).

The patient was discharged with postoperative antibiotics and advised regular follow up and periodical review. Discussion Fibromatosis is a very rare non neoplastic lesion. Due to the rarity and atypical clinical presentation, they may be misdiagnosed clinically as malignancy and subjected to unnecessary surgical intervention. It is a tumor-like enlargement of one or both ovaries due to a non-neoplastic proliferation of collagen-producing ovarian stroma. The patients range from 13-39 years and present with menstrual irregularities, amennorhea or rarely virilization. Lutfu et al1 reported the case of a 19-yearold female who presented with menstrual irregularity, hirsutism and ascites. In yet another case, a 35-yearold woman underwent exploratory laparotomy for ovarian fibromatosis with sclerosing peritonitis and endometriosis.2 This lesion may be seen in association Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

with ascites and pleural effusion to form part of the Meigâ&#x20AC;&#x2122;s syndrome. The other ovarian tumors may be thecoma, cystadenoma or a granulosa cell tumor. Marc Bazot et al3 reported imaging studies in a 25year-old woman,who presented with metrorrhagia and menstrual irregularities. Transabdominal sonography showed well-defined bilateral heterogeneously echogenic masses. CT scan showed bilateral solid homogenous ovarian masses with no fat component. Grossly, 80% of the cases are bilateral. Histopathology shows a proliferation of spindle-shaped fibroblasts with a variable but usually large amount of collagen. Foci of luteinized stromal cells as well as edema may be present. Ovarian architecture is maintained and the fibrous proliferation surrounds follicular derivatives. Nests of sex cord type cells may be present in some cases.4 The sex cord type nests may superficially resemble a Brenner tumor. Ovarian fibromatosis may be distinguished from fibroma, which usually appears in older age groups, is typically non functioning and it almost never contains follicles of their derivatives. Fibromatosis also differs from ovarian edema in that the latter is massive and fibrous proliferation is not observed.5 It differs from stromal hyperplasia in that the latter does not produce abundant collagen and is usually unilateral. The prognosis of the lesion is good and it does not spread beyond the ovaries. References 1. Onderoglu LS, GĂźltekin M, Dursun P, Karcaaltincaba M, Usubutun A, Akata D, et al. Bilateral ovarian fibromatosis presenting with ascites and hirsutism. Gynecol Oncol 2004;94(1):223-5. 2. Frigerio L, Taccagni GL, Mariani A, Mangili G, Ferrari A. Idiopathic sclerosing peritonitis associated with florid mesothelial hyperplasia, ovarian fibromatosis, and endometriosis: a new disorder of abdominal mass. Am J Obstet Gynecol 1997;176(3):721-2. 3. Bazot M, Salem C, Cortez A, Antoine JM, DaraĂŻ E. Imaging of ovarian fibromatosis. AJR Am J Roentgenol 2003;180(5):1288-90. 4. Byrne P, Vella EJ, Rollason T, Frampton J. Ovarian fibromatosis with minor sex cord elements. Case report. Br J Obstet Gynaecol 1989;96(2):245-8. 5. Young RH, Scully RE. Fibromatosis and massive edema of the ovary, possibly related entities: a report of 14 cases of fibromatosis and 11 cases of massive edema. Int J Gynecol Pathol 1984;3(2):153-78.

case report

An Unusual Case of Hepatitis E Induced Fulminant Hepatic Failure Anitha M*, Wilma Delphine Silvia CR**, Vishwanath HL*

Abstract Hepatitis E virus is the leading cause of acute viral hepatitis in the world. Angiomyolipoma is a benign renal neoplasm composed of fat, vascular, and smooth muscle elements. Hemangiomas are the most common tumors of the liver. Situs inversus totalis is a rare anatomic anomaly. We present an unusual case with Hepatitis E-induced fulminant hepatic failure with incidental finding of renal angiomyolipoma, liver hemangioma and situs inversus. Key words: Hepatitis E, angiomyolipoma, hemangioma and situs inversus

epatitis E infection is more prevalent than hepatitis A infection. Hepatitis E virus (HEV) is an enteric virus that usually causes a self-resolving hepatitis; although, it may be fatal, especially in pregnant women.1 Primarily a self-limiting disease, it produces chronic sequelae. A mortality of 20-30% has been reported, particularly in pregnant woman who contract the disease in the third trimester. HEV has been implicated as an important etiological agent for sporadic fulminant hepatic failure (FHF) in developing countries.2 Angiomyolipomas are a benign renal neoplasm composed of fat, vascular, and smooth muscle elements. They are slow growing and truly space occupying, displace the renal parenchyma and distort the collecting system, sometimes causing renal destruction.3 Liver hemangiomas are the most common tumors of the liver. They are usually detected on a routine ultrasound or CT scan and may present with no symptoms.4 Situs inversus totalis is a rare anatomic anomaly with incidence of 1:20,000 in the general population.5

Herein we present a case of a fulminant hepatic failure induced by hepatitis E in a patient with situs inversus totalis and multiple liver and renal angiomyolipomas. Case Report A 65-year-old male presented with a history of generalized weakness, yellowish discoloration of sclera, passing dark-colored urine and loss of appetitie, 15 days prior to admission. He was a known hypertensive since 10 years on treatment and a known dextrocardiac. Personal history: Not a known smoker or alcoholic. Past history: History of exertional dyspnea for past 4-5 years. History of episodic breathlessess for which he was on ayurvedic medications. Family history was not significant. On examination, the patient mas moderately built and nourished, conscious and oriented, afebrile, pulse rate84/min, blood pressure-120/70 mmHg, icterus ++, bilateral pitting pedal edema. Cardiovascular system– S1S2 heard, dextrocardia, Respiratory system–Normal, Investigation at the Time of Admission Urine routine and microscopic examination

*Assistant Professor *Dept. of Biochemistry, Bangalore Medical College and Research Institute **Professor † Professor and Head Dept. of Biochemistry, Vydehi Institute of Medical Sciences and Research Centre, Bangalore Address for correspondence Dr Wilma Delphine Silvia Professor, Dept. of Biochemistry Vydehi Institute of Medical Sciences and Research Centre #82, EPIP Area, Whitefield, Bangalore - 560 066, Karnataka



Color- Pale Yellow



Urobilinogen- Present. Pus cells: 6-8/Hpf



Clarity-slightly turbid



Epethelial Cells: 2–3/Hpf



Albumin- present (+)



RBCs: 0–1/Hpf



Sugar- Nil



Casts



Bile Salts: present (+++)



Crystals



Bile pigments -Present (+++)



Bacterias: not Seen

Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

Case Report 

Random blood sugar-66 mg/dl

Alanine transaminase427mg/dl



Urea-88 mg/ dl



Creatinine-4.24 mg/dl



Total Bilirubin-76.6mg/dl



Directbilirubin-35.0mg/dl



Calcium-8.4 mg/dl



TotalProtein-4.33 g/dl



Total Cholesterol -45 mg/dl



Albumin-2.92g/dl



HDL- 12 mg/dl



Triglyeride-155 mg/dl



Alkaline phosphatase135mg/dl

Gammaglutamyl transferase-144 mg/dl Inorganic Phosphorous12.5 mg/dl

Aspartate transaminase176mg/dl



Hb%-11.5g/dl



PCV- 33.6%



Creatinine-5.13 mg/dl



MCV-96.0(fl)



Na+ -112 mmol/l



MCH-32.9pg



K+ -4.3 mmol/l



MCHC-34.3%



Cl- -78.9mmol/l



Total Leucocytes-8000/cmm



On 3rd day of admission



Neutrophils-74%



Lymphocytes-15%



Eosinophils–1%



Creatinine-06.69 mg/dl



Monocytes–10%



K+-4.1 mmol/l



On 7th day of Admission



BUN-38.7 mg/dl



Creatinine-6.82 mg/ dl



Platelet count– 3.52.000/ cmm Chest PA view– Dextrocardiac Serology: HBsAg (MEIAmicroparticle enzyme immunoassay) Negative

On 2nd day of admission: BUN-39.6 mg/dl

Ammonia -15mol/L and on 6th day of Admission Blood urea nitrogen (BUN)-40.3 mg/dl

Random blood sugar125 mg/dl



Alanine transaminase427IU/L



Total Bilirubin-30.5 mg/dl



Direct Bilirubin-14.4 mg/dl



Total Protein-4.33 mg/dl



Calcium-10.8 mg/dl



Albumin-2.92 mg/dl



Total Cholesterol-65 mg/dl



HDL-20 mg/dl



Triglyerides-200 mg/dl

Uricacid-4.9 mg/dl

Hematological investigations:RBC-3.51million cmm



Alkaline Phosphatase74IU/L Aspartate transaminase176 IU/L

Uricacid-6.0 mg/dl Inorganic Phosphorous9.8 mg/dl

to ICU and arterial blood gas analysis done. There was progressive elevation of serum creatinine/BUN and patient was evaluated for acute renal failure and suggested for ultrasonography (USG) and contrast enhanced computerized tomography of abdomen. Ultrasonography abdomen revealed hemangioma of right lobe of liver, mild hepatomegaly, bilateral grade I nephropathy, BPH grade II, situs inversus totalis and angiomyolipoma in left kidney. Patient was treated symptomatically and the investigations were made one month after the date of admission. MRI of abdomen and pelvis showed mass lesion in the lower pole of left kidney - likely to be a malignant. Hepatic hemangiomas, prostatomegaly with features of bladder outlet obstruction, situs inversus totalis. FNAC was advised and chemotherapy was to be started once the angiomyolipoma was confirmed, and the LFT had come to normal values. But the patient himself discharged against medical advice. Discussion



Anti HCV- Negative



Na+-128 mmol/l



Ig M Anti Virus E –Positive



K+-4.3 mmol/l



Malarial Parasite – Negative



Cl- -94.4 mmol/l

Per abdomen–soft. Bowel sounds +ve, no organomegaly, Central nervous system – coarse tremors of hands, no flaps. Patient was treated with cefoperazone sulbactam IV b.i.d., pantoprazole 40 mg IV, L-ornithine, L-aspartate 4 amp in 5% dextrose over 6 hours IV once-daily. Patient went into coma stage and had altered sensorium. Therefore the patient was shifted Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

The patient was diagnosed to be suffering from viral hepatitis E, as the serum sample was negative for HBsAg and HCV and positive for IgM antibodies of viral hepatitis E. Early in the disease process, the prodromal phase, some patients experience fever, arthralgia, arthritis, rash and angioneurotic edema. These symptoms usually occur 2-3 weeks before jaundice and generally subside before jaundice develops. There may be worsening of anorexia, nausea and vomiting along with scratching and irritated skin lesions and high alanine aminotransferase levels.6 But the most astonishing factor in this particular case was the very 47

Case Report high unexpected levels of total and direct bilirubin i.e, 70 mg/dl and 35 mg/dl. ALT -176U/L, AST-424U/L, even at this high levels the patient was conscious when came to the laboratory for investigations. But on the fifth day of admission, patient became subconscious, was in a confused state and suspected to have hyponatremic encephalopathy and shifted to the ICU. ABG analysis was close to the normal range. Serum urea and creatinine levels were increasing comparatively from day 1 to day 3, whereas urine output was normal, therefore abdominal scan was done to evaluate the cause for non oliguric renal failure. The scan revealed angiomyolipoma of kidney, prostatic hypertrophy and hemangioma of liver. It was confirmed by MRI scan. The described patient never presented with clinical symptoms of angiomyolipomas.7 Hemangiomas of the liver are usually small and asymptomatic. Most hepatic hemangiomas are discovered incidentally at the time of testing for unrelated medical problems. Rarely, larger hemangiomas can rupture, causing severe pain and bleeding into the abdomen that may be life threatening.8 Another incidental as well as remarkable finding in this case is situs inversus, dextrocardia, Only 50% of patients with Kartagener syndrome have situs inversus, patients may also have nasal polyps, an impaired sense of smell, recurrent otitis media, hearing loss, chronic respiratory infections, obstructive lung disease, reduced fertility (females) and/or infertility (males). Each of these conditions is related to impaired cilia or flagella.9 Due to impaired ciliary function, patient had repeated respiratory infections and progressed to chronic obstructive pulmonary disease. Similar to this case there was an incidental finding of renal angiomyolipoma with situs inversus in another case. This finding was also seen in tuberous sclerosis patients, which is an autosomal dominant inheritance and the siblings died of end stage renal failure and epilepsy with the associated feature of renal angiomyolipoma.10 In this case, presence of space occupying lesion such as angiomyolipoma and pre existing grade 1 hypertensive nephropathy may have precipitated the renal failure. However, the situs inversus, angiomyolipoma and liver hemangiomas are incidental findings which are suspicious of tuberous sclerosis complex.

Conclusion It is a rare case of viral hepatitis E with unusual hyperbilirubinemia-induced fulminant hepatitis, which resulted in hepatic encephalopathy and hepatorenal syndrome. On USG, MRI abdomen and pelvis, angiomyolipoma was seen associated with findings like hemangioma of the liver and situs inversus totalis with dextrocardia. Situs inversus totalis is an autosomal recessive inheritance and usually renal angimyolipoma is associated with tuberous sclerosis, which is an autosomal dominant inheritance. So, many more cases have to be evaluated for the type of inheritance. References 1. Mechnik L, Bergman N, Attali M, Beergabel M, Mosenkis B, Sokolowski N, et al. Acute hepatitis E virus infection presenting as a prolonged cholestatic jaundice. J Clin Gastroenterol 2001;33(5):421-2. 2. Sarguna P, Rao A, Sudha Ramana KN. Outbreak of acute viral hepatitis due to hepatitis E virus in Hyderabad. Indian J Med Microbiol 2007;25(4):378-82. 3. W. Dähnert. Dahnert’s Radiology Review Manual 4th edition Lippincott Williams & Wilkins, Philadelphia, 1999:p.761. 4. Liver hemangioma. Available at: http://www.novanews. org. 5. Djohan RS, Rodriguez HE, Wiesman IM, Unti JA, Podbielski FJ. Laparoscopic cholecystectomy and appendectomy in situs inversus totalis. JSLS 2000;4(3):251-4. 6. Choi BY, Nguyen MH. The diagnosis and management of benign hepatic tumors. J Clin Gastroenterol 2005;39(5):401-12. 7. Brodkiewicz A, Marciniak H, Szychot E, Walecka A, Peregud-Pogorzelski J. Angiomyolipomas, renal manifestation of tuberous sclerosis complex in 17-year-old boy--a case report. Ann Acad Med Stetin 2008;54(2):160-5. 8. Blonski W, Reddy KR. Evaluation of nonmalignant liver masses. Curr Gastroenterol Rep 2006;8(1):38-45. 9. Ortega HA, Vega Nde A, Santos BQ, Maia GT. Primary ciliary dyskinesia: considerations regarding six cases of Kartagener syndrome. J Bras Pneumol 2007;33(5):602-8. 10. Neumann HP, Brüggen V, Berger DP, Herbst E, Blum U, Morgenroth A, Schollmeyer P, Wetterauer U. Tuberous sclerosis complex with end-stage renal failure. Nephrol Dial Transplant 1995;10(3):349-53.

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Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

case report

Oocyte Donation: Pregnancy Results and Obstetric Outcome Palshetkar Nandita P*, Pai Hrishikesh D*, Takhtani Manisha***, Rutvij Dalal

Abstract Objective: To evaluate the success rate after oocyte donation and the obstetric and neonatal outcome in these pregnancies. Design: Prospective study Setting: Babies and Us, Infertility, IVF and ICSI centre, Lilavati Hospital, Mumbai Study group: A cohort of 65 women who conceived after oocyte donation. Main outcome measured: Obstetric charts were maintained were all these women and the incidence of obstetric complications and the perinatal outcome was studied. Results: The most common antenatal complications were 1st trimester bleeding (31.2%) and pregnancy induced hypertension (23.4%). The incidence of multiple gestations was 15.6%. No major peripartum events were observed. Conclusion: The incidence of obstetric complications is higher in oocyte donation pregnancies, the complications are usually manageable and most patients have a successful pregnancy outcome. Key words: Oocyte donation, pregnancy, outcome

ocyte donation has now become an essential part of therapeutic armamentarium of many infertility clinics. Since the time of its introduction it has allowed many couples to overcome infertility secondary to factors like advanced age, diminished ovarian reserve, premature ovarian failure, heritable genetic illnesses and surgical menopause. As more and more women delay child bearing these days, the use of donated oocytes and embryos has increased over the years.

such increased occurrence of complications. Some authors have also proposed that the allogenic fetus may predispose the women to hypertensive disorders, intrauterine growth restriction, placental abnormalities and gestational diabetes mellitus.3,4 The present study was a prospective study which analyzed the number of successful pregnancies post oocyte donation and the obstetric and neonatal outcomes in these pregnancies.

Though, it is now an established treatment method, the information regarding the obstetric outcome of these pregnancies is still scarce in literature. Because many of the candidates for oocyte donation are beyond the age of 35 years, concerns have been raised regarding the potential for increased medical and obstetric complications in this cohort. Many authors, so far, have reported a high incidence of complications during pregnancy.1,2 Advanced maternal age, primiparity, and multiple gestations are the various reasons cited for

Study Patients

*Senior, Consultant Infertility Specialist **Past Fellow of National Board Lilavati Hospital and Medical Research Centre, Mumbai Address for correspondence Dr Rutvij Dalal 20, Shreerang Society Near Football Ground Kankaria, Ahmedabad - 380 022

Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

Materials and Methods

This prospective study was conducted at a tertiary centre for infertility and human reproduction. Between years 2004 to 2006, a total of 207 women underwent oocyte donation programme. Of these 207 women, successful pregnancies were achieved in 65. Our study group comprised of these 65 women. Various indications for oocyte donation in these women are summarized in the Table-1. Obstetric charts were maintained for all these women. Registered obstetric variables included incidence of first trimester abortions, preeclampsia, preterm labour and premature rupture of membranes, IUGR, placental abnormalities, oligohydramnios, and gestational diabetes mellitus. Gestational age at the time of delivery and the mode of delivery were recorded. A record of neonatal weight and Apgar scores was also kept. 49

Case Report Table 1. Indication for oocyte Donation Number of Women Primary ovarian failure (Ovarian dysgenesis) Secondary ovarian failure

Premature ovarian failure/ postmenopausal

Surgical castration

Chemotherapy/radiotherapy

Repeated previous IVF failures

Diminished Ovarian reserve

Results The mean age of recipients (who conceived after oocyte donation), at the time of embryo transfer was 38.2 years (range 26-58). Of the 65 women who conceived after oocyte donation, 39 were more than 40 years of age and another three were above 50 years. All women were primigravidas. The baseline characteristics of the parturients are summarized in Table 2.

Hormone Therapy

Antenatal Events and Complications

All patients received exogenous estrogen (estradiol valerate) therapy for endometrial preparation before the embryo transfer. However, the protocol used was different in women with functional and non functional ovaries. Pituitary down regulation with GnRH analogue was done in women who were menstruating, before endometrial preparation with estrogen. In non menstruating women, cyclical hormonal therapy was given till the following criteria were fulfilled:

The major antenatal events are summarized in table3 below. 1st trimester bleeding happened in 20/64 (31.2%) women. 5 women had spontaneous abortions in the first trimester and another one carrying twins aborted at 16 weeks with history suggestive of cervical incompetence. All these women were more than 40 years of age.

Minimum 3 months of bleeding

Uterocervical length ≥5-6 cm Endometrial thickness-8-9 mm Micronised Progesterone was added on the day of donor’s pickup. Day 3 or day 5 embryo transfer was done. Post transfer luteal support was given to all the recipients in the form of estradiol valerate 6 mg/day and micronised progesterone 600mg/day. β-hcg was done on day 14 post transfer to confirm pregnancy. If pregnancy was confirmed, luteal support was continued till 12 weeks of gestation. Antenatal Follow-up

Obstetric charts were maintained for all these women. One woman with confirmed ongoing pregnancy was lost to follow-up. Support during the first trimester included 6-8 mg of estradiol which was given orally for 10-12 weeks, natural micronised progesterone 600 mg/ day for 14-16 weeks and folic acid 5 mg/day. All women underwent triple marker screening test at 15-16 weeks of gestation. All women underwent regular monthly checkups and a close check was kept on haemoglobin, 50

urine and blood pressure. Monthly sonographies were done to confirm the fetal well being.

10(15.6%) women had multiple gestations. Of these 8 women had twin gestation and another two had triplets. One woman with twins aborted at 16 weeks of gestation. Embryo reduction was performed at 11-12 weeks for the two women carrying triplets. There were no complications associated with the procedure. All women underwent prenatal screening for chromosomal abnormalities with maternal serum triple marker test at 16 weeks. Two women tested screen positive. Amniocentesis was advised to these two women for confirming the risk. One woman refused amniocentesis and had a healthy baby. Amniocentesis was performed for the other one and the karyotype was found to be normal. Pregnancy induced hypertension (PIH) complicated 15(23.4%) women. All these women were more Table 2. Baseline Parameters Mean 100% Primi Age (years) Weight BMI (kg/m2)

39.2 (26-58) 52.0 ± 7 22.5 ± 3.6

Parity Chronic hypertension

Preexisting Diabetes

Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

Case Report than 40 years of age. Of these 15 women, 4 women had transient hypertension, 7 women had mild preeclampsia which was controlled with drugs; the remaining four had severe preeclampsia and had to be delivered preterm. All women with severe preeclampsia had IUGR.

Table 3. Antenatal Events

The one woman with chronic hypertension had worsening of blood pressure at around 30 weeks and was delivered preterm at 34 weeks in view of the same.

Transient hypertension

Mild preeclampsia

Severe preeclampsia

Chronic hypertension

Seven out of 64 (10.9%) women delivered preterm. Of these 7 women, 5 were delivered preterm in view of severe preeclampsia. One woman had spontaneous preterm labour at 32 weeks and LSCS was done in view of fetal distress. Another woman with twins had to be delivered at 29 weeks due to IUFD on one twin. Intrauterine growth restriction was observed in 8 women (12.5%). Of these 3 women had twins with mild IUGR, another woman delivered at 29 weeks due to IUFD of one twin and the other twin was growth restricted. The other 4 women had PIH and were delivered preterm between 33-35 weeks. Only two women (3.1%) had gestational diabetes which was controlled by diabetic diet and no drugs were required. Fortunately no adverse pregnancy event cropped up in these pregnancies. Peripartum events and neonatal outcome All women were delivered by caesarean section in view of precious pregnancies. None but one had atonic post partum hemorrhage which was managed conservatively. No life threatening complications were observed in any of the deliveries. A total of 67 infants were born (49 single and 18 twins). There was one still born: this mother had twin gestation with severe PIH which led to IUGR and oligohydramnios. One twin died in utero. Caesarean section was done at 29 weeks. The other twin had Apgar score <7 at 5 minutes, was admitted in NICU for a period of 1 month. All fetus except one had (as mentioned above) had Apgar >7 at 5 minute. No major congenital malformations were observed except for one newborn that had a cleft lip. The two women who tested screen positive for chromosomal abnormalities had healthy babies. Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

Antenatal events 1 trimester bleeding st

Abortion Multiple Gestations Hypertension

No. of women 20(31.2%) 6(9.3%) 10(15.6%) (8 twins; 2 triplets) 15(23.4%)

IUGR

8(12.5%)

Preterm delivery

7(10.9%)

Gestational diabetes

2(3.1%)

Discussion As more and more women delay child bearing these days the use of donated oocytes has increased over the years. Problems with conventional approaches to fertility treatment in older women are as follows:  Oocytes are of poor quality.  Ovulation is less likely.  Corpus luteum may be deficient.  Endometrial receptivity is decreased.  Blastocyst hatching is reduced.  Increased incidence of anembryonic trophoblast development is seen.  Pregnancy may end in abortion and IUFD. The answer to these problems is oocyte donation (OD). OD is highly successful in women of all ages. The use of donor eggs have proved to be a valuable means to achieve pregnancy in many couples with older wives whose egg quality and/or quantity is diminished. Adallah et al reported that pregnancy, implantation and miscarriage rates are independent of the age of the uterus.5 The mean age of women in the present study was 38.2 years (range 26-58 years). First trimester bleeding is a common occurrence in OD pregnancies.2,7 It has been observed to occur in 35-70% of cases and this high incidence is associated with multiple implantations8, early fetal loss9 and endometrial preparation therapy. In the present study, first trimester bleeding occurred in 31.25% women. The incidence of multiple pregnancies in our study was 15.6%, which is comparatively lower than the incidence 51

Case Report cited in other studies.9 Our policy of transferring 2 or 3 embryos at a time can explain this low incidence of multiple gestations. Transfer of more embryos increases the risk of multifetal gestations which are associated with higher obstetric and perinatal complications especially in older women. The most conspicuous complication in oocyte recipients is pregnancy induced hypertension. This is explained by the advanced maternal age, primiparity and the higher incidence of multifetal gestations. In the present study PIH was seen in 15/65 (23%) women which is similar to incidence cited in other studies.1,2,7 The incidence was higher in women with multiple gestations compared from singleton pregnancies. In a recent study conducted by Kreig et al, obstetric complications were compared between women who conceived after oocyte donation, with women more than 38 years of age who conceived after IVF. They observed that Oocyte recipients and autologous oocyte controls had similar rates of complications of prematurity, hypertensive disorders of pregnancy, gestational diabetes, and placental abnormalities. Infant birth weights and gestational age at time of delivery were similar between the two groups.10 PIH has been associated with high rate of premature delivery, IUGR and low birth weight. In our study the incidence of IUGR was more in women with pregnancy complicated by PIH. All women were delivered by Caesarean section because of higher anxiety amongst the mothers and higher level of concern in the medical team. The perinatal outcome was comparable to that after natural/spontaneous conception and most infants did well in there neonatal period with no major complications. Donor oocyte programme has proved to be a boon for many infertile couples and is now one of the essential parts of any infertility clinic. This study suggests that

though the rate of obstetric complications is increased in women undergoing oocyte donation, most of these women thrive well in pregnancy and ultimately have a successful neonatal outcome. This study is however limited by the absence of age matched controls. References 1. Serhal PF, Craft I L. Oocyte donation in 61 patients. Lancet 1989;1:1185-7. 2. Blanchette H. Obstetric performance of patients after oocyte donation. Am J Obstet Gynecol 1993;168: 1803-9. 3. Salho O, Sharma V, Dada T, et al. The influence of donated gametes on the incidence of hypertensive disorder of pregnancy. Hum Reprod 1999;14:2268-73. 4. Toner JP, Grainger DA, Frazer LM. Clinical outcome amongst recipients of donated eggs: an analysis of the US National Experience. 1996-1998. Fertil Steril 2002; 78:1038-45. 5. Abdalla HI, Wren ME, Thomas A, et al. Age of uterus does not affect pregnancy or implantation rates: a study of egg donation in women of different ages sharing oocytes from same donor. Hum Reprod 1997;12:827-9. 6. Pados G, Camus M, Van Steirteghem A, et al. The evolution and outcome of pregnancies from oocyte donation. Hum Reprod 1994;9:538-42. 7. Sauer MV, Paulson RJ, Lobo RA. Pregnancy in women 50 or more years of age: outcome of 22 consecutively established pregnancies from oocyte donation. Fertil Steril 1995;64:111-5. 8. Legro RS, Wong IL, Paulson RJ, et al. Multiple implantation after oocyte donation: a frequent but inefficient event. Fertil steril 1995;63:849-53. 9. GonzĂĄlez MR, Serra V, Garcia-Velasco JA, et al. The `vanishing embryoâ&#x20AC;&#x2122; phenomenon in an oocyte donation programme Human Reproduction 2002;17:798-802. 10. Krieg SA, Henne MB, Westphal LM. Obstetric outcomes in donor oocyte pregnancies compared with advanced maternal age in in vitro fertilization pregnancies. Fertil Steril 2008;90(1):65-70.

Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

infectious disease

Seasonal Influenza: Clinical Crossroads in Diagnosis and Management Sareen D*, Chowdhary A**, Ojha A†, Sareen S†, Jain J†, Krishnaprasad K‡, Jejoe K‡

Abstract Influenza is one of the oldest infections to affect mankind that is often missed clinically or self-treated symptomatically by patients themselves. However, untreated or inappropriate treatment often leads to secondary bacterial complications that can become life-threatening especially in the vulnerable, susceptible population of pediatrics. The concomitant risk factors including low nutritional status or birth weight, allergic history of rhinitis or asthma coupled with poor hygienic practices only seems to compound the matters. The recent outbreaks of influenza in various forms have heightened an increased sense of awareness with several advances being made in the management of influenza with the advent of vaccines and antiviral drugs including oseltamivir and amantadine. Amantadine was the first antiviral agent employed for general use in the management of seasonal influenza A. Despite the regulated availability of newer advanced antiviral agents, international guidelines including WHO (2010) and IDSA (2009) continue to recommend amantadine use for seasonal influenza A (H1N1) even in suspected cases. In such patients due to the concomitant presence of respiratory symptoms at the time of diagnosis, complimentary administration of analgesic, antihistaminic and decongestant along with amantadine would be useful in taking care of the viral load and associated symptoms. Key words: Seasonal influenza A (H1N1), pediatrics, vaccine, oseltamivir, amantadine

nfluenza is an orthomyxovirus that causes respiratory illness associated with significant morbidity and mortality. They have a singlestranded RNA genome and are divided into three genera, A, B and C. Influenza B and C viruses principally infect humans, usually causing only mild illness in children.1 By contrast, the influenza A viruses are maintained in a vast natural reservoir in wild birds, from where they emerge to cause disease in domestic poultry (Bird flu-H5N1), pigs (Swine flu-H1N1) and humans (Seasonal flu-H1N1 and H3N2). The seasonal variant of the H1N1 virus first appeared in 1977, apparently through an accidental laboratory release, and it continues to circulate amongst humans along with H3N2 despite the recent ‘outbreaks’ that we have had in the form of ‘Bird flu’ and ‘Swine flu’.2-4 The seasonal variant remains in circulation as an endemic infection and is often neglected or underdiagnosed due to the overlapping clinical symptoms that it manifests.

Seasonal Influenza: Complications in Children Seasonal influenza, like other viral subtypes, can spread from the upper to the lower respiratory tract to produce primary influenza pneumonia, characterized by respiratory distress, hypoxemia, hypotension and bilateral interstitial infiltrates.1 Bacterial pneumonia can also develop, either simultaneously with or following influenza virus usually caused by Streptococcus pneumoniae. In addition to S. pneumoniae, Staphylococcus aureus, group A streptococci and other pathogens can result in pneumonia, sinusitis or otitis media, as well as exacerbation of underlying health conditions that usually require hospitalization.5 In fact in an observational study by Centers for Disease Control and Prevention (CDC), USA, that was published in JAMA,6 patients with seasonal influenza A were found to have higher rates of hospitalization (3.7%) compared to Swine flu (1.5%) especially in children as shown in Figure 1. Seasonal Influenza: Is it Cold or Flu?

*Professor and Unit Head, MB General Hospital, Udaipur **Director, Haffkine Institute, Mumbai † Intern and Senior Resident, MB General Hospital, Udaipur ‡ Medical Team, Glenmark Pharmaceuticals Ltd., Mumbai

Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

Since, most of the upper respiratory tract viral infections (URTIs) are caused by rhino- and coronaviruses that usually cause self-limiting illness, 53

INFECTIOUS DISEASE

Hospitalization rate (%)

4 3.7 3 2

1.5

1 0

Seasonal influenza

Swine flu

Figure 1. Hospitalization rates in children with seasonal influenza or swine flu.

differentiation based on the clinical symptoms plays an important role in defining an ideal management line for patients suspected to be suffering from influenza. Influenza symptoms often overlap with other respiratory conditions including â&#x20AC;&#x2DC;common coldâ&#x20AC;&#x2122;. The influenza syndrome is however characterized by sudden onset of fever, headache, cough, sore throat, myalgia, nasal congestion, weakness and loss of appetite. This symptom profile including fever is mediated by macrophages that initiate an acute inflammatory phase involving cytokines in response to the invading viruses. The cytokines act to recruit other immune cells, trigger inflammation (sore throat, nasal congestion) and generate systemic symptoms such as fever as shown in Figure 2.7 Cerebral cortex Sensation of chilliness

Vagal nerves

Hypothalamus temperature control center

IL-1 IL-6 TNF IL-10 Macrophages

Seasonal Influenza: Special Issues in Children Children form an important high risk category for developing complications of seasonal influenza since they have an ill developed immune system till the age of 5 years that is usually compounded with low body weight (LBW) at the time of birth.8 Similarly, children with allergic conditions including rhinitis or asthma have a hypersensitive immune system that responds aggressively in form of severe inflammatory reaction that is more likely to result in life-threatening complications, requiring hospitalization. Children play a significant role in influenza transmission leading to school absenteeism. Crowding in schools and lax hygiene practices contribute to spread of the infection in the community.5 Children generally have higher viral load than adults and can shed the virus for at least 10 days thereby contributing to further prolonged spread.9 Seasonal Influenza: Prevention

Shivering

Constriction skin blood vessels FEVER

Figure 2. Fever is caused by cytokines released from macrophages and other immune cells in response to invading viruses.

Again unlike other URTIs, the best predictors for seasonal influenza include a normal chest radiograph result, and absence of leukocytosis.5 This has important implications for clinical management since the only confirmatory test viz. reverse transcriptase polymerase chain reaction (RT-PCR) has several limitations in form of short window time of three days for collection and analyses of respiratory secretions and is not widely available.

Vaccination remains the most effective preventive measure against influenza. Both trivalent inactivated vaccine (TIV), which can be used in persons without a significant allergy to a specific vaccine component, and live attenuated influenza vaccine (LAIV), which can be used only in nonpregnant, otherwise healthy persons aged 2 through 49 years, are available.8 Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

INFECTIOUS DISEASE

Seasonal Influenza: Management In most cases of influenza, management is usually supportive and symptomatic with antiviral therapy being particularly recommended for high-risk patients with seasonal influenza A. Two classes of antiviral drugs are available to treat influenza: Neuraminidase inhibitors (oseltamivir and zanamivir), and M2 inhibitors (amantadine and rimantadine). The neuroaminidase inhibitor, oseltamivir, interferes with release of viral particles from infected cells and is recommended by World Health Organization (WHO)11 for the management of Swine flu (2009 influenza H1N1). Common adverse effects of oseltamivir include nausea, vomiting and neuropsychiatric events particularly in adolescents.12 Amantadine was the first antiviral agent to be licensed worldwide for influenza A infections. It prevents the release of viral RNA genome by inhibiting the M2 ion channel activity of the influenza virus that is essential for its replication. This contributes to the virostatic action of the antiviral drugs including amantadine. Despite its long history of use, amantadine still continues to be recommended by most of the international guidelines. In a recent update of WHO guidelines, 201011 and Infectious Diseases Society of America (IDSA), 2009,13 Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

100 80 Patients (%)

These vaccines usually take upto two weeks before they can offer protection against influenza virus subtypes that are predicted to occur during the influenza season as observed in developed countries. Similarly, these vaccines are recommended for high-risk population including children or individuals (family members, health care providers) in close contact with infants since they could transmit to other vulnerable population including immunocompromised and elderly patients. Despite these recommendations only 15% of the targeted population is being covered in developed countries including USA thereby allowing a considerable sect of the high-risk individuals to be vulnerable to viral infections and its complications.10 Even in the vaccinated individuals, the immunity or protection offered does not last beyond a year of administration.

83.3

60 40 20 0

Amantadine

Figure 3. Percentage of patients with rapid relief at the end of 3rd day with amantadine or NSAIDs.

amantadine has been recommended for cases that are likely or suspected to be due to seasonal influenza A (H1N1) virus even in suspected cases since there is a high-degree of complication rate in case of missed diagnosis or inappropriate therapy. This was further confirmed by an open-label, randomized study by Lao et al14 involving 60 patients suspected to be suffering from seasonal influenza. Patients based on the clinical symptoms of sudden onset of illness with chills and fever and marked prostration, tiredness or body weakness, anorexia, muscular aches/ pains, cough/coryza, flushed face, conjunctival redness and leukopenia were administered either amantadine or nonsteroidal anti-inflammatory drugs (NSAIDs) for four days. Results observed on 3rd day of follow-up are shown in Figure 3. The results showed higher patient responder rates in terms of â&#x20AC;&#x2DC;rapid relief â&#x20AC;&#x2122; from symptoms by 83.3% in the amantadine group as against 16.6% in the NSAID group on the 3rd day of follow-up. In line with the antiviral action of amantadine, nearly all patients on NSAIDs who had symptomatic control had subsequent recurrence of symptoms. This has indirect impact on patient compliance and quality-of-life (QOL) since the continued persistence of symptoms often increases complication rate and therefore the need for antibiotics. In most of the clinical studies, the only side effects noted were dizziness, insomnia and concentration difficulties that usually followed the first or second dose and often subsided with further doses.15 55

INFECTIOUS DISEASE Seasonal Influenza Management with Amantadine: Benefits  Decreases viral load and the related symptoms of inflammation including peripheral airway dysfunction in patients of seasonal influenza (H1N1).16  Virostatic action decreases the high viral load usually observed in children thereby further preventing its spread.15  Virostatic action improves immunological response of the body by decreasing further chances of recurrence or severe infection.17 Seasonal Influenza: Role of Amantadine in Combination Therapy At the time of clinical presentation suspected seasonal influenza cases often show viral symptoms of pyrexia, fatigue along with inflammatory symptoms of rhinitis, sore throat and nose block. Amantadine is highly specific for the influenza A virus, taking care of the viral load rapidly but shows a time lag of 12-15 hours before the concomitant inflammatory symptoms are controlled.18 Similarly, amantadine when given alone shows slower onset of antiviral and therefore antipyretic action. Taking this therapeutic inertia into consideration, Younkin19 recommended combination of acetaminophen with amantadine. Similarly, combination with an antihistamine and decongestant is expected to offer quicker, symptomatic relief of associated symptoms of rhinitis and nasal block at the same time taking care of the insomnia that is likely to be observed with amantadine. This quick action and control of respiratory symptoms obviates the diagnostic or therapeutic inertia involved in the management of seasonal influenza for children who are extremely susceptible to developing severe symptoms or complications rapidly that may require hospitalization. Summary Influenza remains a dynamic infection with several new strains being evolved over the centuries. Though, the new strains of bird flu (H5N1-2003), 56

Swine flu (H1N1-2009) have appeared and caused several deaths, they have consequently been on the decline with virtually no new cases being reported for avian flu. In contrast, the seasonal variant (Seasonal H1N1) that accidentally appeared in 1977 has constantly been in circulation for several decades. In fact, a recent epidemiological study carried out at Haffkine Institute, Mumbai (between August 2009-10) has shown the continued prevalence of the seasonal variant strains. Children particularly in growing years of life or with allergic history including asthma are vulnerable to complications of seasonal influenza rapidly if treated inappropriately with symptomatic drugs alone. In this light, several international recommendations including WHO and IDSA recommend use of amantadine, even in suspected cases of seasonal influenza since the condition is difficult to confirm. However, taking into consideration the concomitant presence of respiratory symptoms including cough, sore throat, myalgia, nasal congestion at the time of diagnosis, complementary administration of analgesic, antihistamine, decongestant along with amantadine offers quicker control of viral and associated inflammatory symptoms that is vital in preventing complications in form of secondary bacterial respiratory complications or hospitalization. This improves the QOL not only in children but also the family or societal members who are in close contact. References 1. Wright PF, Webster RG. Orthomyxoviruses. In: Fields Virology. Knipe DM, Howley PM (Eds.), Lippincott Williams & Wilkins, Philadelphia 2001:1533-79. 2. Rao BL, Banerjee K. Influenza surveillance in Pune, India, 1978-90. Bull World Health Organ 1993;71(2):177-81. 3. Beigel J, Bray M. Current and future antiviral therapy of severe seasonal and avian influenza. Antiviral Res 2008;78(1):91-102. 4. Mukherjee S, Roy S, Dahake R, Chowdhary A. Invitro susceptibility of influenza viruses to amantadine hydrochloride. Bull Haffkine Institute 2011;13(1):58-9. 5. Barry MA. A 29-year-old woman with flu-like symptoms: review of influenza diagnosis and treatment. JAMA 2010;304(6):671-8. 6. Belongia EA, Irving SA, Waring SC, Coleman LA, Meece JK, Vandermause M, et al. Clinical characteristics Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

INFECTIOUS DISEASE and 30-day outcomes for influenza A 2009 (H1N1), 2008-2009 (H1N1), and 2007-2008 (H3N2) infections. JAMA 2010;304(10):1091-8. 7. Eccles R. Understanding the symptoms of the common cold and influenza. Lancet Infect Dis 2005;5(11): 718-25. 8. Seasonal Influenza: Questions and Answers Information about the disease and vaccines. www.vaccineinformation. org/catg.d/p4208.pdf, Item #P4208 (10/09). Accessed on 18th Sept. 2010. 9. Frank AL, Taber LH, Wells CR, Wells JM, Glezen WP, Paredes A. Patterns of shedding of myxoviruses and paramyxoviruses in children. J Infect Dis 1981;144(5):433-41. 10. Lu P, Bridges CB, Euler GL, Singleton JA. Influenza vaccination of recommended adult populations, U.S., 1989-2005. Vaccine 2008;26(14):1786-93. 11. WHO Guidelines for Pharmacological Management of Pandemic Influenza A (H1N1) and other Influenza Viruses . Part I Recommendations, Revised Feb. 2010. 12. Roche Laboratories. Tamiflu (oseltamivir phosphate): capsules and for oral suspension. January 2008. http://www.fda.gov/downloads/Drugs/DrugSafety/ InformationbyDrugClass/UCM147992.pdf. Accessed July 1, 2010. 13. Harper SA, Bradley JS, Englund JA, File TM, Gravenstein S, Hayden FG, et al; Expert Panel of

the IDSA. Seasonal influenza in adults and children - diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2009;48(8):1003-32. 14. Lao LM, Lao ML, Gonzaga Z, Mijares G. Amantadine in the treatment of influenza: an open randomized trial. Phil J Microbiol Infect Dis 1980;9(2):129-34. 15. Junker A, Scheifele D. Prevention and treatment of influenza A with Amantadine hydrochloride. Can Med Assoc J 1980;123(10):961-2. 16. Little JW, Hall WJ, Douglas RG Jr, Hyde RW, Speers DM. Amantadine effect on peripheral airways abnormalities in influenza. A study in 15 students with natural influenza A infection. Ann Intern Med 1976;85(2): 177-82. 17. Nicholson GK, Wiselka MJ. influenza A. BMJ 1991;302:425-6.

Amantadine

for

18. Wingfield WL, Pollack D, Grunert RR. Therapeutic efficacy of amantadine HCl and rimantadine HCl in naturally occurring influenza A2 respiratory illness in man. N Engl J Med 1969;281(11):579-84. 19. Younkin SW, Betts RF, Roth FK, Douglas RG Jr. Reduction in fever and symptoms in young adults with influenza A/Brazil/78 H1N1 infection after treatment with aspirin or amantadine. Antimicrob Agents Chemother 1983;23(4):577-82.

...Cont’d from page 53... 5. Zilkha KJ. Headache and facial pain. Scott Brown’s Otolaryngol 1987;4:341-7. 6. Roger, Martin V, Nauskop A, Rogers A. Efficacy of Rizatriptan 10mg administered early in migraine attack. Headache 2006;46:913-4. 7. Motta E, Rosciszewska D, Miller K. Hemiplegic migraine with CSF abnormalities. Headache 1995;35:368-70. 8. Mathew N, Saper J, Magnis - Millen L. Efficacy and safety of gabapentin in migraine prophylaxis (abstracts) In: 17th Annual Meeting of the American Pam Society, San Diego, Ca. 9. Silber stein SD, Mathew N, Saper J, et al. Migraine Clinical Research group. Botulinum toxin type A as a migraine preventive treatment. Headache 2000;40:445‑50.

10. Schoenen J, Jacquy J, Lenarts M. Effectiveness of high dose riboflavin in migraine prophylaxis. Neurology 1998;50:466-70. 11. Sheftell FD, Rapoport AM, Walker B, et al. Leukotriene antagonists in the prophylaxis of migraine. Headache 1999;39:81. 12. Ostergaard JR. Headache as a warning symptom of impending aneurysmal subarachnoid hemorrhage. Cephalgia 1991;11:53-5. 13. Hockaday JM, Peet KMS, Hockaday TDR. Bromocriptine in migraine. Headache 1976;16:109-14. 14. Rapapart A, Sheftell D, Purdy A. Advanced Therapy of Headache 1999;7:293-301.

Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

Journal of Applied MEDICINE & SURGERY

Case Report

Information for Authors

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Journal of Applied Medicine and Surgery, Vol. 1, Issue 2, January-March 2012

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For Editorial Correspondence Prof. Jayakar Thomas, Please send all manuscripts in a CD to: Prof. Jayakar Thomas, Department of Dermatology and STD, Sree Balaji Medical College & Hospital, #7, Works Road, Chromepet, Chennai - 600 044. Tamil Nadu, India. It is mandatory to send a soft copy to jamsbharath@gmail.com