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Volume 115 u Number 07 u July 2017 u Kolkata


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JOURNAL OF THE INDIAN MEDICAL ASSOCIATION, VOL 115, NO 7,

JULY 2017

Dr K K Aggarwal

Dr R N Tandon

Dr Dilip Kumar Dutta

Dr Kakali Sen

National President IMA

Honorary Secretary General, IMA

Honorary Editor, JIMA

Honorary Secretary, JIMA

CONTENTS Editorial : u Urogynecology — past, present & future — Dilip Kumar Dutta, Manidip Pal ...................7 Original Articles : u Compliance and efficacy of syndromic management of sexually transmitted infections (STI) in women attending Gynec OPD at tertiary care centre — Swati Wankhede, Ashish V Gokhale..................................................................................9 u Optimal first line treatment in neonatal seisure : levetiracetam versus Phenobarbitone — Ram Prakash Saha, Hemant Kumar, Namita Chandra ........................14 Observational Studies : u Allergic rungal rhinosinusitis — our experience — V P Venkatachalam, Prithviraj S .......18 u Effect of hypothyroidism on lipid profile of Type 2 diabetic patients — Soham Mukherjee, Swati Shriwastava, Prakash Keswani, Shrikant Sharma, Ganesh Narain Saxena ...........................................................................22 u Placental blood drainage in the management of the third stage of labour — Nirmala C, Pandu D, Dakshayini B R ............................................................................25 u Role of otorhinolaryngologist in management of head trauma with fracture temporal bone — our experience — M Venugopal, Sreeram P...........................................28 u Double ureter : an important landmark in the field of dissection — M M Patel, T C Singel.....................................................................................................30 Case Report : u Cytodiagnosis of abdominal wall granular cell tumour — an uncommon tumour at a rare site — Madhurima Mitra..................................................33 Wcomments / Feedback 3


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JOURNAL OF THE INDIAN MEDICAL ASSOCIATION, VOL 115, NO 7,

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JOURNAL OF THE INDIAN MEDICAL ASSOCIATION Founder Hony Editor Hony Editor Founder Hony Business Manager Ex-officio Members

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Hony Secretary Hony Associate Editors

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Assistant Secretary

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Sir Nilratan Sircar Dr Dilip Kumar Dutta Dr Aghore Nath Ghosh Dr Santanu Sen, Hony Jt Finance Secretary, IMA (Hqs), Kolkata Dr Santosh Kumar Mandal, Hony. Joint Secretary, IMA (Hqs), Kolkata Dr Kakali Sen Dr Amitabha Bhattacharya Dr Dipanjan Bandyopadhyay Dr Gopal Das

OFFICE BEARERS OF IMA (HQs) National President Dr K K Aggarwal Honorary Secretary General Dr R N Tandon

IMA CGP (Chennai) Dean of Studies Dr V C Shanmuganandan (Karnataka) Honorary Secretary Dr R Gunasekaran (Tamil Nadu)

National President-Elect (2017-2018) Dr Ravi S Wankhedkar (Maharashtra)

IMA AMS (Hyderabad) Chairman Dr Joseph Mani (Kerala) Honorary Secretary Dr Sadanand Rao Vulese (Telangana)

National Vice-Presidents Dr Roy Abhram Kallivayalil (Kerala) Dr K Prakasam (Tamil Nadu) Dr Mahendra Choudhary (Gujarat) Dr Parmanand Prasad Pal (Bihar)

IMA AKN Sinha Institute (Patna) Director Dr Sarbari Dutta (Bengal) Honorary Executive Secretary Dr Raman Kumar Verma (Bihar)

Honorary Finance Secretary Dr V K Monga (Delhi)

JIMA (Calcutta) Honorary Editor Dr Dilip Kumar Dutta (Bengal) Honorary Secretary Dr Kakali Sen (Bengal)

Immediate Past National President Dr S S Agarwal (Rajasthan)

Honorary Joint Secretaries Dr Vinod Khetarpal (Delhi) Dr Anil Goyal (Delhi) Dr Ashwini Kumar Dalmiya (Delhi) Dr Santosh Kumar Mandal (Bengal) Dr B B Gupta (Delhi) Honorary Assistant Secretaries Dr Dinesh Sahai (Delhi) Dr Amrit Pal Singh (Delhi) Honorary Joint Finance Secretaries Dr Manjul Mehta (Delhi) Dr Santanu Sen (Bengal)

Your Health (Calcutta) Honorary Editor Dr Ashok Kumar Chatterjee (Bengal) Honorary Secretary Dr Meenakshi Gangopadhyay (Bengal) IMA N.S.S.S. (Ahmedabad) Chairman Dr Kirti M Patel (Gujarat) Honorary Secretary Dr Yogendra S Modi (Gujarat)

IMA N.P.P.Scheme (Thiruvananthapuram) Chairman Dr Krishna M Parate (Maharashtra) Honorary Secretary Dr Jayakrishnan A V (Kerala) Apka Swasthya (Varanasi) Honorary Editor Dr Vivek Kumar (Uttar Pradesh) Honorary Secretary Dr Sanjay Kumar Rai (Uttar Pradesh) IMA Hospital Board of India Chairman Dr R V Asokan (Kerala) Honorary Secretary Dr Jayesh M Lele (Maharashtra) IMA National Health Scheme Chairman Dr Ashok SAdhao (Maharashtra) Honorary Secretary Dr Alex Franklin (Kerala) IMA National Pension Scheme Chairman Dr Sudipto Roy (Bengal) Honorary Secretary Dr K V Devadas (Kerala)

JOURNAL OF THE INDIAN MEDICAL ASSOCIATION, VOL 115, NO 6,

JUNE 2017

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Editorial

Dr Dilip Kumar Dutta MD, PhD, FRCOG (Hon), FICOG, FIAMS, FICMCH, MAMS, DACOG (USA), DPS (Germany) Chairman, Indian College of Obstetrics & Gynecology (2015) Dean, Indian Academyt of Obstetrics & Gynecology (IAOG) 2017 Vice Chairman, ISAR Bengal 2015-2017 National Editor of 'Jogi Journal' Director, GICE, Kalyani, Nadia, WB Author of 36 books (Obstetrics and Gynaecology) Honorary Editor, Journal of the Indian Medical Association (JIMA)

Dr Manidip Pal MD, FICOG, FICS (USA), Cert. Urogynecologist, Associate Professor, Department of Obstetrics Gynecology, COMJNMH, Kalyani, WB Chairman, India Academy of Obstetrics & Gynecology (IAOG) 2017 Guest Editor, JIMA

Urogynecology — past, present & future

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rogynecology & Pelvic Reconstructive Surgery is a subspecialty of Obstetrics & Gynecology that deals with the disorders of the female pelvic floor such as urinary incontinence, pelvic organ prolapse (bulging out of uterus & /or vagina), fecal incontinence and constipation. It is also known as Female Pelvic Medicine and Reconstructive Surgery. PAST Dr Jack Rodney Robertson (1917-2015) is considered as Father of Urogynecology. In order to examine female urinary tract properly with suitable instruments Jack went to Karl Storz, Germany, who had then just acquired fiber optics and convinced Karl to make the Robertson Female Urethroscope, using carbon dioxide as the dilator . But the journey of urogynecology started many years before Robertson. Howard Kelly in 1893 invented the first air cystoscope. In 1900 he had inserted ureteral catheters using his cystoscope in a female patient in just 3 minutes . PRESENT Urogynecology deals with the problems of female from pelvic ureter to external urethral meatus. Stress urinary incontinence (SUI), overactive bladder (OAB), interstitial cystitis, genito-urinary fistula etc are dealt with. Stress urinary incontinence (leaking of urine whenever there is increase intra-abdominal pressure) is mainly corrected by surgical procedures. But pelvic floor physiotherapy (Kegel’s exercise) and other lifestyle modification is the first line of treatment. Tension-free vaginal tape (TVT), Transobturator tape (TOT), Pubovaginal sling, Burch colposuspension are the popular anti-incontinence surgery. Duloxetine pharmacotherapy can help SUI patient to some extent, but NICE guidelines says – Do not use duloxetine as a first-line treatment for women with predominant stress urinary incontinence . For type III SUI ie ISD (intrinsic sphincter deficiency) bulking agents (bovine collagen, autologous fat, polyacrylamide hydrogel etc) may be injected transurethrally or periurethrally, specially for unwilling or unfit for surgery patients. Overactive bladder (frequency, nocturia, urgency with or without urgency incontinence) is first managed by life style changes and behavioral therapies eg bladder training, pelvic floor muscle training, fluid management, dietary modification etc. Next pharmacotherapy is considered. Oxybutynin, tolterodine, darifenacin, solifenacin, trospium etc are usually prescribed medicines. Nowadays Mirabegron (ß3 adrenoreceptor agonist) has put a significant impact in the OAB management. It is the only drug targeted to induce relaxation of the detrusor muscle during storage phase, while other antimuscarinic agents are directed to inhibit involuntary detrusor contraction. Mirabegron increases the bladder capacity with no change in micturition pressure and residual volume . Local estrogen therapy may be considered for the postmenopausal OAB patient with vaginal atrophy. It is relatively easy to treat non-neurogenic OAB in compare to neurogenic OAB. Sacral nerve stimulation may be considered in refractory OAB cases. Surgery is the last resort – augmentation cystoplasty, urinary diversion etc may be done. 1

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While diagnosing voiding dysfunction, urine culture & sensitivity, to rule out infection, is the foremost test. Frequency by volume bladder dairy - 3 day bladder dairy, if not, at least 2 day bladder dairy, is very helpful in diagnosis and follow up management. Ultrasonography is done to know post void residual volume of urine, posterior urethrovesical angle, pubic symphysis to bladder neck distance - during normal and valsalva etc. Concept of volume ultrasonography is very helpful in this regard. Urodynamic study (UDS) is not mandatory for all the urogynec patients. We can diagnose and treat the patients basing on history, physical examination and other investigations. But in complicated cases urodynamic study has a great role. Addition of EMG (Electromyography) to UDS has allowed us to differentiate the neuromuscular etiologies. Video urodynamics and Ambulatory urodynamics are other noteworthy armamentarium. Cystoscopy is a routine affair in urogynecology. Bladder wall mass, diverticulum, interstitial cystitis, ureteric reflux, funneling of bladder neck etc. can be diagnosed easily. Painful bladder syndrome (Interstitial cystitis) (PBS/IC) is one of the very worse condition in urogynecology. There is recurring discomfort or pain in the bladder and pelvic region. As PBS varies so much in symptoms and severity, most researchers believe - it is not one, but mixture of several diseases. Amitriptyline is commonly used oral drug. Oral or intravesical Pentosan polysulphate sodium (PPS) installation is a good treatment option. Dimethyl sulfoxide (DMSO), hyaluronic acid intravesical therapy can also be considered. Non responders can be offered Botulinum toxin intravesical injection. Sacral neuromodulation is found to be effective in 1/3rd of refractory cases. Genito-urinary fistula is the challenging condition to the urogynecologist. It may be urethro-vaginal fistula, vesicovaginal fistula, uretero-vaginal fistula, vesico-uterine fistula etc. The secret of successful repair lies on tension free repair and insertion of interposition graft with viable vascularity. FUTURE Future of urogynecology is blooming as women living in the geriatric ages are increasing day by day. Nowadays a woman spent 1/3rd of her lifespan in post menopausal age and many urogynecological disorders developed during post menopausal period. So the budding doctors interested in this field should undergo proper training in the certified centers under the guidance of trained urogynecologist. International Continence Society and International Urogynecological Association (ICS/IUGA) guidelines should be followed to propagate the knowledge in correct way. Stem cell therapy may exert a beneficial effect via the secretion of bioactive factors that direct other stem and progenitor cells to the area of injury, which possess antiapoptotic, antiscarring, neovascularizing and immunomodulatory properties. Local injections of mesenchymal, muscle-derived and adipose-derived stem cells have shown successful outcomes in animal models of mechanical, nerve or external urethral sphincter injury in SUI. Direct injection of mesenchymal and adipose-derived stem cells into the bladder in animal models of overactive bladder have also demonstrated efficacy. Early clinical trials using stem cells in human for SUI treatment have also shown good results with minimal adverse effects. Though many issues are to be answered, still stem cell therapy for voiding dysfunction have a good potentiality . A proper bio-marker for overactive bladder is need of the hour. Researches are going on worldwide. Hope to get good news in near future, so that preventive measures may be offered to those women who may become victim of the disease later. National urogynecology & pelvic reconstructive surgery registry needs to be created to include indications, complications, and outcomes of all anti-incontinence and reconstructive pelvic surgery. 5

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Original Article Compliance and efficacy of syndromic management of sexually transmitted infections (STI) in women attending Gynec OPD at tertiary care centre 1

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Swati Wankhede , Ashish V Gokhale

Syndromic management of sexually transmitted infections is a simple and effective method for the treatment of symptomatic sexually transmitted infections in the limited resourced settings. It is a prospective study conducted in department of obstetrics and gynecology in Sir’ Takhtsingh hospital in Bhavnagar from august 2010 to july 2011. Total of 219 patients presenting to Gynec OPD with the complaint of vaginal discharge, lower abdominal pain, pruritus vulvae, and urinary symptoms were included in the study as per the inclusion criteria. The most frequent presenting symptom of STI in the women is vaginal discharge (84%) followed by lower abdominal pain (48%) of women. The most frequent associated complain was pruritus vulvae (35%) of women and 4% of women were asymptomatic. The most frequent kit prescribed was kit ll indicating higher percentage of patients with mixed infection, trichomoniasis and candidiasis. Infertility was seen in 7% of women seeking treatment for STI which is significant. Past history for STI and treatment taken for STI was seen in almost 20% of the patients is an important association indicating re-infection or incomplete treatment. Percentage reduction of symptoms on follow up. Women with vaginal discharge had 56.54% relief of symptoms on day seven which increased to 80% upto day fourteen. Out of 200 total patients prescribed treatment as per NACO guideline 171 took complete treatment with complete cure after 2 weeks of treatment in 75% patients and in partially cured patients confirmation by laboratory diagnosis in indicated patients in our study had added to the efficacy of the syndromic approach, and thereby increase the cure rate to about 93-95%. The compliance rate was good with syndromic approach accounting for about 82% and no drug side effect was reported at all. The main factor for the partial cure was partial treatment accounting for 62.16%, followed by Lack of condom usage or inconsistent condom use (54.05%), Promiscuity and multiple sexual partners (24.3%) For vaginal and cervical infections, the development of rapid, accurate diagnostic tests is the priority for improved care in the future that will improve STD detection in resource-poor settings which will make the syndromic management of STI much promoted by WHO to be the best and effective first step to contain STI in all the developing and under resourced setting of the world. [J Indian Med Assoc 2017; 115: 9-13]

Key words : Sexually transmitted infection, syndromic management. 1 2 3 4 5

Dr Jack Rodney Robertson Obituary. The Santa Barbara News-Press. http://www.legacy.com/obituaries/ newspress/ obituary.aspx?pid=174617125 Young HH. A Surgeon’s Autobiography. New York: Harcourt, 1940. https://www.nice.org.uk/donotdo/do-not-use-duloxetine-as-a-firstline-treatment-for-women-with-predominant-stress-urinary-incontinence Sacco E, Bientinesi R. Mirabegron: a review of recent data and its prospects in the management of overactive bladder. Ther Adv Urol 2012; 4: 31524. Tran C, Damaser MS. The potential role of stem cells in the treatment of urinary incontinence. Ther Adv Urol 2015; 7: 22-40.

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exually transmitted infection’s (STI’s) are the majorpublic health problem in both the developed and developing countries. The world health organisation WHO estimated in 1999 there were 340 million new cases of curable STI's world wide and almost 1 million new infections occur every day . CDC 2010 estimates 19 million new cases in US alone . It is estimated that India has a high incidence of STI’s with an annual growth rate of 5%, there are about 40 million new STI cases every year . Sexually transmitted Infections (STIs) are a major contributor to the morbidity and mortality of populations, particularly because their presence increases the risk of HIV transmission twofold to 20-fold . Timely diagnosis and treatment are critical com1

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Disclaimer The information and opinions presented in the Journal reflect the views of the authors and not of the Journal or its Editorial Board or the Publisher. Publication does not constitute endorsement by the journal. JIMA assumes no responsibility for the authenticity or reliability of any product, equipment, gadget or any claim by medical establishments/institutions/manufacturers or any training programme in the form of advertisements appearing in JIMA and also does not endorse or give any guarantee to such products or training programme or promote any such thing or claims made so after. — Hony Editor

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Department of Obstetrics & Gynaecolgy, Government Medical College, Bhavnagar 364002 1 MBBS, Senior resident 2 MD (Obstet & Gynaecol), Professor & Head

ponents in the prevention of the spread of STIs. To date, STIs are most accurately detected using technologically advanced diagnostic techniques. These techniques are often expensive and necessitate trained staff, laboratory equipment, specific storage and transportation conditions, and treatment delays until patients return for their results. Unfortunately, countries that are hardest hit by STIs lack the resources to implement or maintain “high-tech” STD programs .This dilemma prompted the development of the syndromic management to improve STD diagnosis and treatment in resource-poor settings . Syndromic management is based on the idea that a specific set of signs and symptoms constitutes a syndrome and indicates the presence of a certain class of infection. A combination of treatments are then prescribed that are effective against the most common organisms that cause this syndrome. Syndromic approach offers a quick and effective treat5

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ment of STI’s at first visit itself. It ensures early diagnosis and treatment of STI’s in order to reduce both its transmission to others and to minimise their sequel. It also involves educating the general population on the dangerous of high risk sexual behavior and persuading them to use condoms and limit their sexual partners. Out of 7 STI syndromes vaginal discharge is the most common and comprises about 85% of women having STI. Vaginal discharge is often polymicrobial in nature and treatment of only one of the most apparent cause may lead to clinical manifestations of the other causes thus it is important to treat Vaginal discharge and lower abdominal pain as a most clinically apparent cause of a disease. Algorithms or flowcharts have been developed for the diagnosis of the major syndromes of STDs: urethral discharge (UD), genital ulcer disease (GUD), vaginal discharge (VD), and lower abdominal pain (LAP) . Because STDs often lack obvious signs and symptoms, researchers developed systems of patient risk-score assessments to improve the accuracy of syndromic algorithms for the detection of cervical and vaginal infections . This study aims at assessing the efficacy, acceptability and compliance of syndromic management and find out the causes of treatment failure if any in patients treated with syndromic approach. 7

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MATERIALS AND METHODS

It is a prospective study conducted in department of obstetrics and Gynecology at Sir’Takhtsinghji hospital in Bhavnagar from august 2010 to july 2011. All women coming to gynec OPD with complain vaginal discharge and lower abdominal pain or both and fulfilling the inclusion criteria was enrolled in the study. The women coming to gynec OPD for any other complain and found to have vaginal discharge or otherwise asymptomatic were also included in this study. All women were explained about the type and design of the study and due consent was taken in their vernacular language. The women were explain about the pathological nature of the discharge, modes of transmission, need for prompt intervention and significance of the treatment of their sexual partner for complete relief of symptoms in a simple language. Inclusion criteria : • Women in the reproductive age (15-45 years) complaining of vaginal discharge, lower abdominal pain or both. Exclusion criteria : • Pregnant women • Puerperal women • Women who received any treatment for vaginal discharge in last 2 weeks • Women with h/o drug allergy. Detailed history as regards menstrual history, Obstetrics history, history of any medical condition like DM, anemia, hypertension, tuberculosis, malignancy, drug allergy, any immunosuppressive therapy etc. was recorded in a Performa. Past history of sexually

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transmitted infection was asked in great detail and nature of complains and treatment taken was recorded. Sexual history was taken in detail with great emphasis given on counseling of the women and her partner together at first visit and subsequent follow-up visits. Couple was explained to take complete treatment, follow abstinence or use condom during the treatment after thorough counseling for better management. Detailed gynecological examination was carried out severity and type of discharge was noted. The patients thus examined were prescribed treatment according to the syndromic approach depending upon their specific syndromes. Women with vaginal discharge syndrome were given kit I or kit II & their partners were also given kit I and kit II respectively. Women with lower abdominal pain syndrome were given kit VI and their husband were prescribed kit I as per the NACO guidelines. The women were asked to keep abstinence or use condom during the period of 14 days to prevent re infection with their partners. The couple was asked to swallow the drugs on same day and return with the empty packets on the follow up on 7 day to check the compliance. On follow on 7th and 14th day women were inquired about the relief of symptoms and their response was noted. Including use of condoms and abstinence observed. On follow up if the women did not get relief of her symptoms then vaginal discharge was sent in the laboratory in Sir T. Hospital Bhavnagar, which is NABH accredited for specific lab diagnosis were gram staining, KOH mount, wet mount vaginal swab culture and sensitivity was done. The study was approved by Institutional Review Board at Govt. medical College & Sir T hospital,Bhavnagar. Data thus collected was analysed as per outcome analysis. Response to the treatment was noted as follows : • Complete treatment: treatment taken by patient as well as her sexual partner both. • Partial treatment : treatment taken by the patient only where as the partner remains untreated. • Complete cure : patient relieved of her symptoms after treatment by more than 75% . • Partial cure : patient relieved of her symptom after treatment by less than 50% . • No relief : patient continues to have symptoms after treatment or reduction in symptoms less than 25%. th

symptomless nature of STI caused by gonorrhea and Chlamydia which are the major culprit of all STI and its complications (Figs 1&2). In this study kit 2 containing 1tablet secnidazole 2 gram and capsule fluconazole 150 mg stat and single dose was most frequently prescribed followed by kit 1 containing 1 tablet azithromycin 1 gm and tablet cefixime 400 mg stat and single dose followed by kit 6 containing 1 tablet cefixime 400 mg stat and tablet metronidazole 400 mg BD for 14 days and capsule doxycycline 100mg BD for 14 days respectively was prescribed. The percentage of mixed infections, trichomoniasis and candidiasis is found to be higher in this study attributed to the maximum prescription of kit ll as per NACO guideline to the patient accounting for almost 55% of the three kits prescribed. Combination kits are cheaper, effective, given in single dose orally with efficacy of 95- 98%. The single dose combination kit allows good compliance, complete treatment at the first visit thus preventing the spread of sexually transmitted disease and HIV . Fig 3 shows percentage reduction of symptoms on follow up -. women with vaginal discharge had 56.54% relief of symptoms on day seven which increased to 80% upto day fourteen. Out of total no of 200 patients included in the study and prescribed treatment as per the NACO guidelines for the treatment of STI, 171 patients took complete treatment ie, the patient as well as the partner was treated; 27 patients took the partial treatment ie, women treated and the partner declined to take treatment. Thirty seven patients of the compeletely or partially treated patient were partially cured and were subjected to the specific lab diagnostic tests for the further confirmation and management of the STI syndrome; 5 patients out of 200 had no relief of symptoms at all as per treatment prescribed according to syndromic approach that accounts only to 2.5%, which indicates the high efficacy of the syndromic approach in the management of STI. 79% of the patient treated with the syndromic approach had complete cure of the STI syndrome without being subjected to the specific lab diagnostic tests and further treatment . 6

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The most important cause of partial cure was partially treated women whose partner remained untreated and accounted for almost 62.16%. Lack of condom usage or inconsistent condom use (54.05%) was the second most significant factor contributing to the partial cure indicating re Fig 2 — Frequency of Kits prescribed infection with the particular STI and a major hindrance in increasing the efficacy of the syndromic approach in the management of STI. Promiscuity and multiple sexual partners contributing to the partial cure was about 24.3% of the patients who were partially cured and thus contributing to the spread of STI as the untreated sexual partner continues to spread infection and re infection. One of the most important factor as regards compliance was; only 7 patients reported poor compliance to drugs prescribed in the syndromic approach. Poor compliance was seen in patients treated with kit 6; reason being the long duration of treatment ie, for 14 days and multiple drug regimen with multiple doses. Comparatively not a single case of poor compliance was reported when patient was prescribed kit l and kit 2 because of the simple and single stat dose regimen . Factors associated with STI-The most significant factor associated with STI was found to be past infection with STI or treatment taken in the past for STI accounting for almost 20.6%. Followed weakened immune system due to the general condition like anemia , diabetes, and TB, causing increase chances of contacting STI easily. Promiscuisity (4.5%) of the patients only indicating deceiving of the sexual history and multiple sexual partners. Three per cent (6 patients) of the patients were found to be immunocompromised : out of which 4 patients were found to be sero positive and 2 patients were on immunosuppressive therapy. In this study the association of HIV and STI could not be 10

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OBSERVATION AND DISCUSSION

Out of 219 patients enrolled in the study, 19 patients were lost on subsequent follow up on day 7 and day 14 and thus were excluded from the study. In present study vaginal discharge (84%) was the most common complain of the women with sexually transmitted infection, followed by lower abdominal pain (48%) of the women, pruritus vulvae (35%), urinary symptoms (25%) and only 4% of the women were asymptomatic; found to have STI on clinical examination. Less number of asymptomatic women may be attributed to the subclinical nature of the infection and relatively

Fig 1 — Frequency of presenting symptoms (As patients presented with more than one symptom at the time of first visit)

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Fig 3 — Percentage reduction of symptoms on follow-up


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found out due to small number of the subjects included in the study. Infertility was associated with the STI in 7% of patients which is significant and one of the major complication of STI. The mixed infection was found to be highest among the different STI causing organism; indicating the polymicrobial nature of the vaginal discharge, accounting for almost 28%. Tricomoniasis (23%), bacterial vaginosis (18.5%), and candidiasis (17.5%) were also found to be the most frequent STI causing organisms respectively (Figs 4-7). Gonorrhea and Chlamydia were found to be relatively less frequent (6.5%) in this study main reason being the inert and subclinical nature of these infections having tendency to go unrecognized and lack of specific diagnostic lab testing in the underesourced settings. Lab diagnosis in partially cured patients :Specific lab test Outcome (positive test) VDRL 00 KOH mount 11 Gram stain 03 Wet mount 12 HIV test 04 Vaginal swab 30 Partially cured patients were subjected to specific lab diagnostic tests as described above , out of which 30 patients had vaginal swab culture and sensitivity revealing growth of different organisms indicating secondary bacterial infections along with specific STI causing organism in association. The various secondary bacterial infections found was staphylococcus aureus, streptococcus, peptostreptococcus, e coli, kleibsella, pseudomonas etc. Twelve patients showed mobile trichomonads on wet mount. Eleven patients showed fungal elements on KOH mount and Three had gram stain positive

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with 2 showing intracellular gram negative diplococci s/o gonorrhea and 1 showing gram positive cocci in cluster s/o secondary bacterial infection with streptococcus. None of the patients had VDRL reactive showing decrease in incidence of syphilis as a result of better diagnosis and treatment available. Among the 200 patients only 4 patients were found to be sero positive for HIV that is only 2% of the patient with STI were HIV infected. Most frequent STI in our study was found to be mixed infections accounting for about 28%. Most common infection was bacterial vaginosis seen in 32.26% of patients. Mixed infection includes gonorrhea, Chlamydia and secondary bacterial infections which are sub clinical in nature and difficult to diagnose and harbors a burden of over all 70% of all STI. DISCUSSION

Syndromic management is cost effective and highly recommended in terms of prevention of further transmission of STI relapse, STI related complications, development of resistance and even transmission of HIV. WHO’s simplified generic tool includes flowcharts for women with symptoms of vaginal discharge and/or lower abdominal pain. While the flowcharts for abdominal pain are quite satisfactory, those for vaginal discharge have limitations, particularly in the management of cervical (gonococcal and chlamydial) infections . The WHO has created algorithms for use in settings with and without the ability to perform either speculum examinations or laboratory diagnostics . Research has shown that the algorithms for diagnosing cervicitis or vaginitis have low predictive values and for that reason training and improved quality of history taking are recommended . The sensitivities for the algorithms for vaginal discharge ranged from 73% to 93% among women presenting with 8

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symptoms of vaginal discharge, and from 29% to 86% among women not presenting with symptoms . Syndromic management along with confirmation by lab diagnosis in indicated patients in our study had added to the efficacy of the syndromic approach, and thereby increase the cure rate to about 93-95%. There remains an urgent need for the development of an affordable, rapid, and effective diagnostic technique that will improve STD detection in resource-poor settings . The syndromic management of vaginal discharge among women seeking family planning and other reproductive health services should focus on vaginal infections, thus enhancing quality of care and addressing women’s concerns about their health . To improve the sensitivity and specificity of the VD algorithms to detect cervical infection, risk determinants and risk scores have been incorporated into many algorithms. Risk determinants are characteristics that are most closely associated with cervical or vaginal infection in a specific population, such as specific demographic factors, sexual history, laboratory diagnostic results, and physical signs and symptoms . The addition of speculum examination to an algorithm may increase or decrease the likelihood that a person will be diagnosed as having a cervical infection . Specific algorithms that were tested incorporate simple laboratory tests to aid in the diagnosis of infection. Some of the tests that are implemented include microscopy to look for trichomonads indicating an infection with Trichomonas vaginalis, polymorphs indicating cervical infection, or a positive rapid plasma reagin test result indicating infection with syphilis. Several of these tests are not highly sensitive or specific, and algorithms that incorporate these tests are still compared with more sensitive and specific goldstandard laboratory tests . Further study will determine whether rapid diagnostic tests, such as urine-based leukocyte-esterase dipstick tests, in conjunction with risk scores may help improve the sensitivity of algorithms to detect cervical and vaginal infection . Single dose TF (tinidazole + fluconazole) is as effective as multiple dose MC (metronidazole +clotrimazole) in the syndromic management of vaginal discharge,even among women with HIV infection.Given its low price and easier adherence, TF should be considered as a first line of treatment for vaginal discharge syndrome . Problems that may further decrease the effectiveness of algorithms in the field include clinicians’ resistance to implementing syndromic management, incorrect drug treatment and prescription, inadequate counseling regarding STDs, (eg, partner notification, condom usage), poor provider training, lack of supplies, and clinic populations who either are lacking prevention knowledge or are unable to protect themselves. The use of algorithm should be supported by periodic assessment of the locally prevalent STIs. An understanding about the relative prevalence of various RTIs/STIs in the area could then be used to improve the training of health care personnel for effective use of algorithms for locally prevalent infection . 11,12

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Fig 4 — Outcome amongst partially treated patients

Fig 5 — Reasons for partial cure (More than one reason was seen in patients)

Fig 6 — Factors associated with STI

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Fig 7 — Frequent STI on presumptive diagnosis

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ACKNOWLEDGEMENT

Authors acknowledge Project Director, Gujarat AIDS control Society,for providing the drugs as per NACO, Guidelines. We acknowledge Dean, Medical College, Bhavnagar & Medical Supdtt. Sir T Hospital for allowing us to carry out this study. REFERENCES 1 Global prevalence and incidence of selected curable STIs, overview and estimates. Geneva, World Health Organisation, 2001. 2 Report on the global HIV/AIDS epidemic. Geneva, UNAIDS, 2000. 3 AIDS epidemic update. December 2004. Geneva, UNAIDS/WHO, 2005; 85. 4 Fleming D, Wasserheit J — Epidemiological synergy to public health policy and practice: the contribution of other sexually transmitted diseases to sexual transmission of HIV infection. Sex Transm Infect 1999; 75: 3-17. 5 Holmes KK, Ryan C — STD care management. In: Holmes KK, Sparling PF, Mardh P-A, eds. Sexually Transmitted Diseases. New York: McGraw-Hill, 1999. 6 World Health Organization — Management of patients with sexually transmitted diseases. World Health Organ Tech Rep Ser 1991; 810: 1-103. 7 Vuylsteke B, Laga M, Alary M — Clinical algorithms for the screening of women for gonococcal and chlamydial infection: evaluation of pregnant women and prostitutes in Zaire. Clin Infect Dis 1993; 17: 82-8. 8 Mayaud P, Grosskurth H, Changlucha J — Risk assessment and other screening options for gonorrhoea and chlamydial infections in women attending rural Tanzanian antenatal clinics. Bull World Health Organ 1995; 73: 621-30. 9 Guidelines for the management of sexually transmitted infections- world health organization 2003. 10 Jacques Pepin, Francois sobela, Nzambi Khonde, Thomas Agyarko –Poku — Syndromic management of vaginal discharge using single dose treatments: a randomized controlled trial in west Africa- Bulletin of the World Health Organisation 2006; 84: 729-38. 11 Vishwanath S, Talwar V, Prasad R, Coyaji K, Elias CJ, I de Zoysa — Syndromic management of vaginal discharge among women in a reproductive health clinic in India. Sex Transm Infect 2000; 76: 303-6. 12 R George, K Thomas, S P Thyagarajan, L Jeyaseelan, A Peedicayil, V Jeyaseelan, and George S and the STD Study Group — Genital syndromes and syndromic management of vaginal discharge in a community setting. Int J STD AIDS June 2004; 15: 367-70. 13 Behets F, Desormeaux J, Joseph D — Control of sexually transmitted diseases in Haiti: Results and implications of a baseline study among pregnant women living in Cité Soleil shantytowns. J Infect Dis 1995; 172: 764-71. 14 Ryan C, Courtois B, Hawes S — Risk assessment, symptoms, and signs as predictors of vulvovaginal and cervical infections in an urban US STD clinic: implications for use of STD algorithms. Sex Transm Infect 1998; 74: S59-76. 15 Pettifor, Audrey MPH; Walsh, Julia MD, DTPH; Wilkins, Victoria MPH; Raghunathan, Pratima PhD, MPH -How Effective Is Syndromic Management of STDs?: A Review of Current Studies - Sexually Transmitted Diseases: August 2000; 27: 371-38. 16 Jesse L. Clark1, Andres G. Lescano2, Kelika A. Konda1, Segundo R. Leon3, Franca R. Jones4, Jeffrey D.Klausner5, Thomas J. Coates1, Carlos F. Caceres3 for the NIMH International Collaborative HIV/STD Prevention TrialSyndromic Management and STI Control in Urban Peru. September 2009 | Volume 4 | Issue 9 | e7201 PLoS ONE | www.plosone.org


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JOURNAL OF THE INDIAN MEDICAL ASSOCIATION, VOL 115, NO 7,

JULY 2017

Original Article Optimal first line treatment in neonatal seisure : levetiracetam versus phenobarbitone Ram Prakash Saha1, Hemant Kumar2, Namita Chandra1 To compare the efficacy of levetiracetam and phenobarbitone for treatment of neonatal seisures in term and near-term neonates. Open labeled randomised controlled trial. This study was carried out on 80 newborn babies suffering from clinically apparent seisure admitted in NICU of Department of Paediatrics of Patna Medical College and Hospital. All term and late pre-term neonates admitted with clinically apparent seisures and not having any transient metabolic disorders (hypoglycemia or hypocalcemia) were randomly assigned. Levetiracetam (n=42) at a intravenous doses of 10 mg/kg LEV were gradually increased to 30 mg/kg over 3 days with a further titration to 45-60 mg/kg and Phenobarbitone (n=38) at a intravenous dose of 20 mg/kg/dose over 20-30 min. Neonates whose seizures were not controlled by the assigned drug were then crossed over to be treated with other drug in same dose. Baseline characteristics were comparable in both groups. Seisures were controlled in 28 of the 42 (66.6%) neonates who received levetiracetam, as compared to 31 of 38(73.8%) neonates who received phenobarbitone (p>0.05). Short term adverse effects (cardio-respiratory depression and sedation) were noted in 11/38 babies in Phenobarbital group in comparision to 1/42 babies in Levetiracetam group (p<0.05). Long term neurodevelopemental complications were noted in 5/25 babies in levetiracetam group compared to 9/23 babies in phenobarbital group (p<0.05) at 1 year of age. Levetiracetam and phenobarbitone, both were equally effective in control of clinical seisures irrespective of the etiology, but levetiracetam is superior in term of short and long term neurodevelopemental outcome than phenobarbitone. [J Indian Med Assoc 2017; 115: 14-7]

Key words : Seisure, Levetiracetam, Phenobarbitone, EEG.

N

eonatal seisures are the most frequent clinical manifestation of central nervous system dysfunction in the newborn,with an incidence of 1.5-3.5/1000 in term newborns and 10-130/1000 in preterm newborns . Neonatal seisures have deleterious effects on the developing brain, so their prompt recognition and treatment is crucial to prevent future adverse effects. The most common causes of seisures in the neonatal period are hypoxic–ischemic encephalopathy, central nervous system infections, infarctions, hemorrhages and metabolic abnormalities. There are currently no evidence-based guidelines for evaluation and management of neonatal seisures. Available data indicate that phenobarbital (PB) remains the first-line treatment for neonatal seisures . Yet, a recent Cochrane Review concluded that “there is little evidence to support the use of any of the anticonvulsants currently used in the neonatal period” . Conventional treatment (Phenobarbital and phenytoin) only achieves clinical control in 50%-80% of cases and is even less effective in controlling most neonatal electroencephalographic seisures . On the other hand, there is increasing concern over the long term adverse effects of phenobarbital, since it was shown to increase neuronal apoptosis in 1

2

3

4

Department of Paediatrics, Patna Medical College & Hospital, Patna 800004 1 MBBS, Junior Resident 2 MD, Assistant Professor

animal models and induce cognitive impairment in infants and toddlers . Levetiracetam (LEV) is an effective and well-tolerated antiepileptic drug currently licensed for the treatment of neonatal seisure. There are hardly any reports of severe, life threatening side effects, while most frequently observed adverse effects included somnolence and behavioral problems . Furthermore, LEV presents a favorable profile regarding neuronal apoptosis: in contrast to most other established antiepileptic drugs it was not found to increase apoptosis in the developing rodent brain or interfere with neuroprotective up-regulation of hypoxia inducible transcription factor 1 (HIF-1a) and it was shown to decrease neurodegeneration in rodent models of hypoxia/ischemia or epilepsy . We intended to compare efficacy of levetiracetam and phenobarbitone in the treatment of clinically apparent seisures in term and late pre-term neonates. 5

6

7

8

9

10

11,12

MATERIALS AND METHODS

Study Design : This is aopen-label randomised controlled study. This study included 80 neonates (57 males and 23 females) admitted in NICU of Upgraded Department of Paediatrics of Patna Medical College and Hospital suffering from

clinically aparent seisure in the period between December 2013 to September 2014. Block randomisation of 80 numbers in blocks of 4 was done by using computer generated random numbers. They were put in serially numbered opaque envelopes and sealed. This was done by a person not involved in study. These pre-numbered sealed envelopes were opened to determine the anticonvulsant to be given to the baby. Our trial was an open label trial, so the doctors and nursing staff were aware of the treatment assignments. However, the EEG technicians and neurologist reporting the EEG were blinded to the intervention. Inclusion Criteria : • All term or near term neonates (>35 weeks of gestation) admitted with clinically apparent seizures after ruling out hypoglycemia, hypocalcemia and other metabolic disorders. • Clinical criteria for diagnosis of neonatal seisures were: (i) clonic movement which could be unifocal, multifocal or generalised (ii) tonic posturing with or without abnormal gaze (iii) subtle seisures and spontaneous paroxysmal, repetitive motor or autonomic phenomenon like lip smacking, chewing, paddling, cyclic movements or respiratory irregularities. Exclusion Criteria : • Seisure responding to correction of hypoglycemia, hypocalcemia or any other metabolic disorder. • Preterm neonates (<35 weeks of gestation) • Babies with major congenital malformation or myoclonic jerk • Infants who were intubated at admission to NICU. Protocol : Details of name, age, sex, weight, head circumference and length were recorded on a pre structured proforma. Patency of airway, breathing and circulation was ensured based on standard guidelines . After a cannula was secured, blood sugar, serum calcium and blood for other tests was drawn. Hypoglycemia was defined as blood sugar <45mg/dL . Hypocalcemia was defined as ionised calcium <4 mg/dL (1mmol/L) in late preterm and less than 1.2 mmol/L (ionic) in term neonates . If seisures persisted even after correction of hypoglycemia and hypocalcemia, babies were randomised to either Levetiracetam(LEV) (plan A) or Phenobarbitone (plan B). In plan A, baby was loaded with Initial intravenous doses of 10 mg/kg LEV and gradually increased to 30 mg/kg over 3 days with a further titration to 45-60 mg/kg .Cardiac rate, rhythm and blood pressure was monitored during the infusion. If seizure persisted, the babies were crossed over to IV phenobarbitone. In Plan B, babies were loaded with injection phenobarbitone at 20 mg/kg slow IV infusion over 30 min under cardiorespiratory monitoring. If seisure persisted, baby crossed over to receive IV levetiracetam in 13

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above dose. If seizure persisted after two drugs, baby was reloaded with IV phenobarbitone @10 mg/kg each to a maximum of 40 mg/kg and then a third line drug like midazolam was used iv at 0.1mg/kg/dose. Administration of the drug was discontinued if respiratory depression (cessation of respiration for more than 20 seconds, or less than 20 seconds associated with cyanosis or bradycardia), hypotension (mean blood pressure less than 35 mm of Hg) or bradycardia (heart rate <80/minute) developed after use of either of the drugs. Once the baby was seisure-free for five days, anticonvulsants were stopped in the same order as they were started. IV phenobarbitone and levetiracetam were changed to oral once baby was on 50% of enteral feeds. Phenobarbitone and levetiracetam in respective group were stopped last at discharge if neurological examination was normal and EEG demonstrated no electrical seisures. If neurological examination or EEG was not normal or not done then levetiracetam and phenobarbitone in respective group were continued after discharge and baby was reevaluated at the age of 3, 6 and 12 months for anticonvulsant efficacy, neurodevelopmental outcome and other complications. Outcome : • Primary outcome variable of this study is cessation of clinical seisure activity (No seisure for 5 days) . • Secondary outcome variables were (i) Time taken to control seisures. (ii) Survival at discharge (iii) Short term adverse effect and long term neurodevelopment outcome at 12 months (Amiel-Tieson method), and (iv) EEG control of seisures. Neurological examination was done in all babies at discharge. It included examination of overall activity, response to stimuli, ability to suck and swallow, active and passive tone of neck and trunk muscles and neonatal reflexes (Moro, traction and habituation). Examination at 3, 6 and 12 months was done by examination of tone by Amiel Tieson method (adductor angle, popliteal angle, dorsiflexion angle and scarf sign). Achievement of milestones like social smile, recognition of mother, neonatal reflexs (Moro’s and grasp), head circumference and persistence of seisure were evaluated. For those babies who could not come for follow up, telephonic interview of parents and local practitioners was conducted. They were asked about age, specific developmental milestones, weight gain, feeding, persistence of seisures and over all perception of parents about neurological status and development. Neurodevelopment outcome was considered abnormal if tone of baby was outside of Amiel Tieson score range and if no social smile or recognition of mother was noted by 3 months Statistical analysis : Statistical analysis was done using intention to treat


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analysis. Results were analysed using SPSS 13 software. Continuous data with normal distribution were analysed by student t test and non-normally distributed data by Mann-Whitney Test. Categorical data was analysed by chi-square test or Fischer exact test, where applicable.Statistics all data were expressed in mean standard deviation. P< 0.05 was considered as significant. RESULT

A total of 80 babies with clinically apparent seizures were screened during the study period. Out of them,42 babies were randomised to levetiracetam group (Group A) and 38 babies were randomised to phenobarbitone group (Group B). Baseline characteristics and seizures characteristics were comparable in both groups (Table 1). In case of multiple types of seisures in a baby, he was classified on the basis of first seisure type only. Cessation of clinical seisure was observed in 28 of the 42 (66.6%) neonates who received levetiracetam and 31 of 38 (73.8%) neonates receiving phenobarbitone first (p>0.05). Babies in whom seisure control was not achieved with first drug, after cross-over, seisure control was achieved in 38/42 (90.4%) of the neonates assigned to receive levetiracetam first and 36/38 (94.7%) of those assigned to receive phenobarbitone first(p>0.05). After maximum dose of phenobarbitone, seisures were controlled in 40/42 (95.2%) in levetiracetam group and 37/38 (97.3%) in phenobarbitone (p>0.05). Median (range) time taken to control all seisures was 30 min (10 minutes – 48 hours) in hypoxic ischemic encephalopathy (HIE) stage II, 60 minutes (10 minutes – 6 days) in HIE stage III, 52 minutes (15minutes-24 hours) in meningitis, and 11 hours (30 minutes-3 hours) in intracranial hemorrhage. There was no significant difference in seisure control in the two groups (P >0.05).Short term adverse effects (cardio-respiratory depression and sedation) were noted in 11/38 babies in Phenobarbital group in comparision to 3/42 babies in Levetiracetam group (p<0.05). Out of 80 babies enrolled in the study, 18 babies expired during NICU stay (10 babies in Phenobarbitone group and 8 babies in Levetiracetam group, p>0.05) and 62 were discharged. 12 of these 18 deaths were in babies with HIE stage III. Of the remaining, 4 were in HIE stage II, 1 had sepsis and 1 had intraventricular haemorrhage. None of these mortalities were within 4 hours of giving drugs so likely to be unrelated to drugs used, but due to underlying condition. Among 62 discharged babies, 14 were lost to follow up, and 48 babies (25 babies in Levetiracetam group & 23 babies in Phenobarbitone group) were followed at 6 months and 12 months. At 12 months, in Levetiracetam group, 2/25 babies presented developmental delay and 1/25 babies presented with mental retardation and 2/25 babies multiple comorbidities. In the Phenobarbital group, 5/23 were

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diagnosed with developmental delay, 3/23 babies with mental rertardation while 1/12 had comorbidities (p<0.05) (Table 2). After clinical control of seizures, EEG was done in 54 babies out of which 49(90.7%) had normal EEG record and 5(9.2%) had abnormal EEG record. There was no significant difference in incidence of abnormal EEG records in the two groups. The common abnormalities noted were electrical spikes, and background abnormalities like “burst suppression” pattern or low electrical voltage. DISCUSSION

Our study demonstrated that levetiracetam and phenobarbitone, both were equally effective in control of clinical seisures in term or near term neonates irrespective of the etiology ,but levetiracetam is superior in term of short term adverse effect and long term neurodevelopemental outcome than phenobarbitone. The most common anticonvulsant used initially in the newborn period for seisure treatment is intravenous Phenobarbitone although there are many concerns regarding the short-term adverse effects of PB as well as long-term effect on neurocognitive development. Intravenous phenytoin and benzodiazepines are commonly employed as second-line intravenous medications in the treatment of neonatal seisures . The adverse effects of phenytoin are well known and include cardiac arrhythmias and hypotension. In comparision,levetiracetam is equally effec 14

15

Table 1 — Baseline characteristics of study population Parameters Gestational age (wk) Weight (kg) Male sex28(66.6%) Etiologies of seizure Hypoxic Ischaemic Encephalopathy(HIE) : Sepsis Intracranial bleed Type of seizure : Subtle Tonic Clonic *

*

tive in controlling seisure and is safe due to its linear pharmacokinetics (half-life of 7 hours), rapid absorption (30 min), nonhepatic elimination, lack of protein binding (<10%), no known interactions with other antiepileptic drugs . Khan O et al studied 22 neonates on treatment with levetiracetam and showed that seisures control in majority (19) of neonates was achieved by 1 hour. All patients were seisure-free by 72 hours. No significant side effects were reported by them . Abend et al retrospectively studied 23 neonates with seisures who received levetiracetam. They observed 50% seisure reduction within 24 hours. Levetiracetam was associated with a greater than 50% seisure reduction in 35%, including seisure termination in 30% Shoemaker MTet al reported three neonates with various etiologies of refractory neonatal seisures and seisures were controlled with levetiracetam. They did not report any adverse effects and these babies remained seisure-free thereafter . Ramantani et al studied 38 neonates with seizures treated with Levetiracetam and reported that it is safe and effective in controlling neonatal seizures. Various studies have reported a wide range for levetiracetam dosage ranging from 10 to 80 mg/kg/day . Merhar et al studied the pharmacokinetics of Levetiracetam in neonates. They noted that neonates had lower plasma clearance, higher volume of distribution, and longer half-life as compared with older children and adults. The encouraging results obtained in our study illustrate the efficacy and safety of levetiracetam as first line treatment in neonatal seizures. However, Double blind prospective controlled studies and long term evaluation of cognitive outcome is called for, in order to establish a reasonable alternative to phenobabitone. Lack of blinding of clinical outcomes, inability to monitor serum drug level and cerebral function were the limitation of our study. 16

8 9

18

10

19

11

20

12 13

18,19,20,21

Phenobarbitone group(n=38)

38.6(1.45) 2.71(0.4) 29(76.3%)

38.09(1.87) 2.55(0.05)

23 (54.7)

20(52.6)

3

18(42.8) 1(2.38)

16(42.1) 2(5.26)

4

21(50) 18(42.8) 3(7.14)

20(52.6) 16(42.1) 2(5.26)

5

Table 2 — Short and long term effect comparision between two groups Outcome Levetiracetam Phenobarbitone p value Group Group Short term adverse effect : Respiratory depression 1(n=42) 7(n=38) 0.024 Sedation 0(n=42) 4(n=38) 0.047 Hypotension 0(n=42) 5(n=38) 0.020 Long term Outcome at 3 month : Developmental delay 2(n=25) 8(n=23) 0.033 Mental retardation 1(n=25) 6(n=23) 0.044 Co-morbities 1(n=25) 6(n=23) 0.044

7

17

Levetiracetam group (n=42)

in No. (%); *mean standard deviation

6

1 2

REFERENCES Volpe JJ — Neonatal seizures. In: Volpe, editor. Neurology of the newborn. 5th ed, vol 2008. Philadelphia: WB Saunders; 2008; 203e44. Bartha AI, Shen J, Katz KH — Neonatal seizures: multicenter variability in current treatment practices. Pediatr Neurol 2007; 37: 85e90. Booth D, Evans DJ — Anticonvulsants for neonates with seizures. Cochrane Database Syst Rev 2004; 4: CD004218. Boylan GB, Rennie JM, Pressler RM — Phenobarbitone, neonatal seizures, and video-EEG. Arch Dis Child Fetal Neonatal Ed 2002; 86: 165e70. Bittigau P, Sifringer M, Ikonomidou C — Antiepileptic drugs

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and apoptosis in the developing brain. Ann N Y AcadSci 2003; 993: 103e14. Camfield CS, Chaplin S, Doyle AB — Side effects of phenobarbital in toddlers. J Pediatr 1979; 95: 361e5. Opp J, Tuxhorn I, May T — Levetiracetam inchildren with refractory epilepsy: a multicenter open label study in Germany. Seizure 2005; 14: 476e84. Manthey D, Asimiadou S, Stefovska V — Sulthiame but not levetiracetam exerts neurotoxic effect in the developing rat brain. ExpNeurol 2005; 193: 497e503. Trollmann R, Strasser K, Keller S — HIF-1-regulated vasoactive systems are differentially involved in acute hypoxic stress responses of the developing brain of newborn mice and are not affected by levetiracetam. Brain Res 2008; 1199: 27e36. Hanon E, Klitgaard H — Neuroprotective properties of the novel antiepileptic drug levetiracetam in the rat middle cerebral artery occlusion model of focal cerebral ischemia. Seizure 2001; 10: 287e93. Lo¨ scher W, Ho¨nack D, Rundfeldt C — Antiepileptogenic effects of the novel anticonvulsant levetiracetam (ucb L059) in the kindling model of temporal lobe epilepsy. J Pharmacol Exp Ther 1998; 284: 474e9. Marini H, Costa C, Passaniti M — Levetiracetam protects against kainic acid-induced toxicity. Life Sci 2004; 74: 1253e64. JeevaSankar M, Agarwal R, Aggrawal R, Deorari AK, Paul VK — Seizures in the newborn. Indian J Pediatr 2008; 75: 149-55. Sankar R, Painter MJ. Neonatal seizures: after all these years we still love what doesn’t work. Neurology 2005; 64: 776e7. Painter MJ, Scher MS, Stein AD — Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med 1999; 341: 485e9 Radtke RA — Pharmacokinetics of levetiracetam. Epilepsia 2001; 4: 24e7. Pin˜ a-Garza JE, NordliJr DR, Rating D, Yang H, Schiemann- Delgado J, Duncan BLevetiracetam N01009 Study Group — Adjunctive levetiracetamin infants and young children with refractory partial-onset seizures. Epilepsia 2009; 50: 1141e9. Khan O, Chang E, Cipriani C, Wright C, Crisp E, Kirmani B — Use of intravenous levetiracetam for management of acute seizures in neonates. Pediatr Neurol 2011; 44: 265-9. Abend NS, Gutierrez-Colina AM, Monk HM, Dlugos DJ, Clancy RR — Levetiracetam for treatment of neonatal seizures. J Child Neurol 2011; 26: 465-70. Shoemaker MT, Rotenberg JS — Levetiracetam for the treatment of neonatal seizures. J Child Neurol 2007; 22: 958. Ramantani G, Ikonomidou C, Walter B, Rating D, Dinger J — Levetiracetam: Safety and efficacy in neonatal seizures. Eur J Paediatr Neurol 2011; 15: 1-7. Merhar SL, Schibler KR, Sherwin CM, Meinzen-Derr J, Shi J, Balmakund T, et al — Pharmacokinetics of levetiracetam in neonates with seizures. J Pediatr 2011; 159: 152-4.


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Observational Study Allergic rungal rhinosinusitis — our experience 1

V P Venkatachalam , Prithviraj S

2

Allergic fungal rhinosinusitis is immunologically mediated disease. It is a relatively newly recognised disease entity that makes it a great deal of interest. It is a Non-invasive form of fungal sinusitis with great propensity of recurrence. A well understanding of this underlying disease process has led to an evolution in the treatment. In our study we are formulating the etiopathogenesis and management protocol for Allergic fungal rhinosinusitis on the basis of our experience in our institution Dr Ram Manohar Lohia Hospital, New Delhi. [J Indian Med Assoc 2017; 115: 18-21 & 24]

Key words : Allergic fungal rhinosinusitis, steroid, Itraconazole.

A

llergic fungal rhinosinusitis (AFRS) is the most com-mon but least understood type of fungal sinusitis. Over the last few years, different subcategories have been identified further adding to the confusion. The incidence of AFRS appears to be impacted by geographic factors. Fungi causing allergic fungal sinusitis are usually dematiaceous (dark colored) or hyaline (lightly colored) species, are ubiquitous in nature, and typically demonstrate septate hyphae forms (Fig 1). Fungi belonging to the dematiaceous family are the most common agents implicated in AFRS worldwide; especially Bipolaris species was the most common fungi isolated . But in India there is universal isolation of Aspergillus flavus as noted by Dhiwakar et al , which is probably attributed to hot and dry climatic conditions here. The disease is related to hypersensitivity to aerosolised environmental fungi. This is followed by Gel and Coombs type 1 (IgE) and probably type 3 (Immune complex mediated) reaction that triggers an intense eosinophilic inflammatory response and result in eventual product of this process->Allergic Mucin . The production of allergic mucin is unique to Allergic Fungal Sinusitis and essential for definitive diagnosis . The mainstay of treatment for AFRS is Surgery along with oral/systemic steroid and antifungal agent. The aim of this study was to evaluate etiopathogenesis and management of diagnosed cases of AFRS. 1,2

3

4

5

MATERIAL AND METHODS

This prospective study was conducted on 40 diagnosed cases of Allergic Fungal Rhinosinusitis who were admitted in department of Otorhinolaryngology and Head & Neck Surgery, Dr Ram Manohar Lohia Hospital New Delhi, for Functional Endoscopic Sinus Surgery during a

Department of ENT, Safdarjung Hospital & Vardhman Mahavir Medical College, New Delhi 110029 1 MS, DLO, MNAMS, FACS, FICS, FIAO, Professor and Head 2 MBBS, 3rd year Postgraduate, Department of ENT, PGIMER and Dr RML Hospital, New Delhi 110001

period of 2 years. Detailed history was taken regarding symptoms, atopy, family history of atopy and systemic illness. A detailed otorhinolaryngological examination was carried out. The investigations carried out includes absolute eosinophil count, total serum IgE, fungal serology, nasal swab or nasal wash for direct microscopy (Fig 2), fungal culture and s e n s i t i v i t y, allergic mucin a n d radiological examination. The preoperative diagnosis of AFRS was based on the triad of nasal Fig 1 — Slide from a patient of AFRS showing polyposis, typical branched septate hyphae characteristic Computerised Tomography (CT) scan picture (Figs 4&6) and type-I hypersensitivity on history and serology. All the patients were p u t o n preoperative course of antibiotic, Fig 2 — Magnified view showing fungal antihistaminic hyphae on 10% KOH and steroids for one week. A diagnostic nasal endoscopy was performed on all the patients before the start of surgery to stage them as per Kupferberg endoscopic staging system. All the patients were subjected

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to Functional Endoscopic Sinus Surgery ( F E S S ) . Intraoperative l y t h e specimen ( a l l e r g i c Fig 4 — Pre operative NCCT Coronal cuts (Patient 1) mucin, debris, and polyps) was sent for histopathological evaluation and fungal culture and sensitivity. Postoperatively the patients were put on broad spectrum antibiotics, steroids (oral and intranasal) and antifungal therapy. Follow-up was done for six months after the surgery. Patients were evaluated initially at weekly interval for the first month and later on at two weekly intervals for three months. Subjective improvement was analyzed based on the improvement of Fig 6 — Pre operative NCCT preoperative symptoms. Coronal cuts (Patient 2) Patient were asked whether the symptoms were cured, improved, remained same or worsened. Objective improvement was analysed after doing n a s a l endoscopy at each follow up and using Kupferberg e n d o s c o p i c Fig 5 — Postoperative NCCT Coronal cuts (Patient 1) staging to grade the improvement. Repeat radiological evaluation (Figs 5,7,8), total serum IgE and nasal swab or wash for 10% KOH and allergic mucin was done for the evaluation of recurrence. Data was analysed using SPSS version 17. For descriptive statistics, mean was calculated. Sensitivity, specificity and predictive values Fig 7 — Postoperative NCCT Coronal cut (Patient 2) were also calculated for the preoperative investigations done. For comparisons the student’s t- test and chi – square test were used where applicable. The level of significance was set at <0.05. RESULTS

Majority of patients in our study were in the

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age group of 20-40 years, disease presented in 25 (62.5%) patients. Male to female ratio was 5:3. Nasal obstruction was present in 40 (100%) patients and Rhinorrhea was present in 32 (80%) patients. Fig 8 — Postoperative NCCT History of allergy Axial cut (Patient 2) present in 25 (62.5%) patients. Raised Total Eosinophil Count (TEC) and raised Absolute Eosinophil Count (AEC) was present in 36 (90.0%) and 37 (92.5%) patients respectively. Serum IgE was raised in 37 (92.5%) patients. Mean values of TEC, AEC and total serum IgE were 11.03%, 795.0 /mm and 1324.13 IU/ml respectively. In our study skin prick test for type- I hypersensitivity against fungal antigen was positive in 9 (22.5%) patients. On nasal Endoscopy, polyps were presented in all 40 (100%) patients. Allergic mucin and Fungal debris were present in 34 (85.0%) and 30 (75.0%) patients respectively. On the basis of Kupferberg staging 17 (42.5%) patients had stage II and 33 (82.5%) patients had stage III polyps. On comparison of serum IgE and Kupferberg staging, it was concluded that mean value of serum IgE increases with increase in the Kupferberg stage (Correlation coefficient is 0.2). It is found on correlation study between serum IgE and Absolute Eosinophil Count (AEC) that both parameters have liner relationship (p-value <0.007). In our study Anterior & Posterior Ethmoid sinus was most commonly involved in 37 (92.5%) patients. Allergic mucin containing eosinophil with or without Charcot-leyden’s crystals and nasal polyps were most consistent intraoperative finding being present in all 40 (100%) patients. Fungal debris was present in 31(77.5%) patients. But hexagonal Charcot-Leyden’s crystals were present in only 26 (65%) patients, considered as minor criteria for diagnosis of AFRS. In our study fungal serology was positive in 34 (85%) patients and 32 (80%) patients had nasal smear positive for fungal hyphae. The various fungi causing AFRS in our study included Aspergillus flavus in 27 (67.5%), Aspergillus fumigates in 7 (17.5%) patients, 2 (5%) patient is positive for Dematiaceous fungi (1 is positive for Fussarium and other is Curvularia). There was negative fungal culture in 4 (10%) patients. Out of 40 patients, one patient was culture positive but negative for sensitivity against antifungal drugs. All 40 (100%) patients were improved subjectively after surgery and medical management. Out of 40 patients 3 (7.5%) patients developed Synechae. Nasal discharge was present in two patients after three month of Endoscopic Sinus Surgery. Patients who have nasal discharge were positive for fungal hyphae on 10% KOH. Out of them one patient also has sphenoidal mucocele on CT scan. These two patients (5%) were defined as recurrence. 3


JOURNAL OF THE INDIAN MEDICAL ASSOCIATION, VOL 115, NO 7, DISCUSSION

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AFRS group. Dhiwakar et al reported characteristic hyper density seen in 100%. Five of their 20 patients (25%) with AFRS had orbital spread, 4 (20%) patients also showed intracranial invasion. Malm et al and Kupferberg et al on basis of Nasal endoscopy and Anterior rhinoscopy divided the patients of nasal polyps into 3 grades in relationship to fixed anatomic landmarks. According to this staging system 42.5% and 57.5% patients of our AFRS were of grade II and grade III respectively, while there was no grade I polyp associated with AFRS (Table 1, Fig 3). In our study grade III polyps were predominantly associated with mean serum IgE value of 1592.5IU/ml, where as grade II polyps had serum IgE mean value was 961.0 IU/ml. P-value for this study was 0.23 and correlation coefficient is 0.2 suggest linear relationship. This shows that the role of serum IgE is not limited to identify patients with type I hypersensitivity, but can also be used to predict advanced disease requiring an aggressive therapy and in future can be used as a prognostic marker in the follow up period. When two or more positive tests were used to identify patients with AFRS it was revealed that presence of allergic mucin and CT scan heterogeneity were able to diagnosis maximum number of AFRS cases (100% in our study). Whereas raised Aspergillus specific serum IgE along with heterogeneity in CT scan were positive for AFRS in only 92.5% patients. The triad of allergic mucin, Raised serum IgE and CT heterogeneity had a sensitivity of 90%, specificity of 100% and a positive predictive value of 100% which led to the inference, that presence of allergic mucin on nasal smear examination in a patient of nasal polyposis whose CT scan reveals heterogeneous involvement and has elevated serum IgE is the best diagnostic modality preoperatively. This was in contrast to Dhiwakar et al ,who advocated that presence of nasal polyps, heterogeneous foci in CT scans and elevated Aspergillus specific serum IgE as the most sensitive (70%) for preoperatively identifying patients with AFRS. The diagnosis of AFRS was confirmed on basis Table 1 — Correlation between of histopathological serum IgE and Malm Staging e x a m i n a t i o n . O n Malm Serum IgE p-value histopathology the staging Mean Std Dev presence of allergic II 961 842.11 0.23 1592.5 2000.95 mucin was seen every III patients (100% cases), presence of eosinophilic infiltrates (100%), non invasive fungal hyphae (85%) and Charcot–Leyden’s crystals (65%) patients. These histopathological Fig 3 — Correlation between serum IgE 11

The exact etiopathogenesis of allergic fungal sinusitis thought to be due to hypersensitivity to inhaled fungal antigens which results in a self propagating cycle of mucosal edema and stasis in nasal cavity ultimately resulting in polyp formation. The preoperative differentiation would facilitate selection of the appropriate surgical procedure. The differentiation of AFRS from invasive fungal disease would also enable the surgeon to use systemic and local steroids in the preoperative and immediate postoperative period. In our study age of the patients ranged from 12-55 years, with maximum numbers of patients in 3rd and 4th decade. The patients of AFRS were younger with mean age of 32.15 years. Majority of patients with AFRS were <40 years (77.5%).Only 4 patients (10%) of AFRS were more than 50 years. Male to female ratio is 5:3. Nasal obstruction and chronic nasal discharge were the most frequent symptoms seen in our study 100% and 80% respectively followed by headache and anosmia. Proptosis was seen in 12.5% of AFRS patients (5 cases). More than half of patients (70%) with AFRS presented with duration of symptoms <18 months. There are 4 (10%) patients of AFRS also had history of Asthma. Association of AFRS with asthma was similar to study of Dhiwakar et al who said asthma was present in 10% of AFRS patients. Skin prick test for fungal specific antigen was positive in 11(27.5%). Pre-Op Allergic mucin was present in 34 (85) who ware later diagnosed as AFRS, Which was higher than 60% allergic mucin positive cases in study by Ravi Kumar et al .Fungal hyphae in nasal smears were demonstrated in 34 (85%) patients compared to 20% incidence in the series reported by Ravi Kumar et al . In our study elevated level of AEC presented in 36 (90%) patients and mean value of AEC was 795.0 cells/µl. Wicker GM had an average AEC of 528 cells/µl in his study. Serum IgE>150 IU/ml (Normal value 0-150 IU/ml) and Aspergillus specific Serum IgE (Positive fungal serology) was seen in 92.5% and 85% of AFRS patients respectively, on preoperative serological evaluation. AFRS patients had a mean value of serum IgE was 1324.1 IU/ml, ranging from 113-10167 IU/ml. Similar findings were observed by Goh et al (56.7% with elevated Serum IgE and 1307 IU/ml mean serum IgE). This is further corroborated by our findings of elevated Aspergillus sp. Serum IgG in 90% cases. Allergic mucin was 100% sensitive and 100% specific in diagnosing cases of AFRS whereas presence of fungal Hyphae in nasal smears had a sensitivity of 85%. CT scans are considered as the cornerstone for establishing a diagnosis of AFRS. Areas of hyper attenuation on CT scan are thought to be characteristic of AFRS and have been identified as one of the essential criteria for its diagnosis . In our study, CT scans showed presence of heterogeneity in all cases of AFRS, Bone erosion (in 17.5% cases), thinning of lamina (Orbital involvement) seen in 17.5% and intracranial extension in 2 (5 %) patients was seen in the 3

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and Malm Staging

findings were also observed by Ravi Kumar et al in their series of AFRS patients. They reported eosinophillic infiltrates in 90%, Charcot–Leyden crystals in 20%. Positive fungal cultures were obtained in 90% (36) patients of our cases. Manning et al yielded positive cultures in 64% cases and Goh et al had only 36.75% patients with positive fungal cultures. It is notable that positive fungal culture does not confirm the diagnosis of AFRS, nor does a negative culture rule it out. Fungi may proliferate as saprophytic growth in diseased sinuses. Furthermore mycology laboratories may vary in capability and specimen handing, which significantly influences the rate of positive fungal cultures reporting . Hence, presence of allergic mucin on histopathological examination should be considered as the most reliable indicator of AFRS. Use of allergic mucin as diagnostic criteria for AFRS, also has an added advantage as it helps us in saving upon time as fungal cultures usually yield results after 4 weeks. Aspergillus flavus was the most common isolated fungi seen in 27 cases (67.5%) and Aspergillus fumigatus was positive in 7 (17.5%). In our study 2 (5%) patients were positive for Dematecious fungi one is Fussarium and other is Curvularia. This was not consistent with the previously reported universal isolation of Aspergillus specimen by Dhiwakar et al . Rupa et al reported that Aspergillus specimen were the most common fungi isolated (95.8%) in a series of 24 patients with AFRS. This predominance of Aspergillus species has been attributed to the dry and hot climatic conditions in these areas. In contrast, AFRS in west is generally associated with demetiaceous fungi which have been found to be greater in the humid climate. All our 40 patients were taken up for combined approach that was surgical as well as medical management. Functional endoscopic sinus surgery with removal of all disease mucosa was done on all the 40 patients which is the standard treatment advocated by Kupferberg et al (1997) , Schubert et al (2000) and Marpel et al (2001) . Surgery was combined with pre operative and post operative oral corticosteroids. Pre operative steroids were given one week prior to the surgery to decrease the mucosal edema and intra operative bleeding. Post operative oral corticosteroids were given for at least three weeks with tapering dose in all the patients. Anti fungal agents such as itraconazole, the newest available azole antifungal agent has activity against Aspergillus. Itraconazole are fairly benign, orally delivered antifungal agents had been started post operatively for at least six months. This agent is less toxic and it decreases the antigenic load. Denning et al (1991) , reported the patients with allergic fungal sinusitis who were treated with itraconazole 200 mg twice daily demonstrated decrease in total IgE production and oral steroid requirements. In our study, we also followed our patients for six months and found negative for 10% KOH. In our study after six month follow ups, only 2 patients (6.67%) showed recurrence. Rest of our patients showed 6

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no recurrence and are doing well with our management approach that is surgical as well as medical. Currently available literature regarding the long term clinical behaviour of allergic fungal sinusitis has focused predominantly on the issue of recurrence. According to Kupferberg (1997) recurrence rate depend on the type of treatment and surgery for Allergic Fungal Sinusitis without post operative medical management leads to recurrence rates of up to 100% depending on the expert experience. Previous studies and our present study defines that combined approach surgery followed by post operative oral and intranasal corticosteroids with oral antifungal, is the best treatment to prevent recurrence of this disease. 13

CONCLUSION

In the light of our findings we feel that postoperative monitoring beside nasal endoscopy and CT scan should include serum IgE since it reflects a good prognostic indicator of eradication of disease. If the post-operative value of serum IgE level is raised then the dosage of steroid can be increased and given for a longer duration. Also for achieving best result, combined Surgical and medical treatment with regular follow-up constitute the mainstay of management of AFRS with minimum recurrence. In our series only 2 patients (5%) showed recurrence which was managed successfully and both these patients are without any recurrence of disease at the last follow up at 6 months. REFRENCES 1 Manning SC, Schaefer SD, Close LG, Vuitch F — Culture positive allergic fungal sinusitis. Arch Otolaryngol Head Neck Surg 1991; 117: 174-8. 2 Corey JP, Delsupehe KG, Ferguson BJ — Allergic fungal sinusitis: allergic, infectious, or both? Otolaryngol Head and Neck Surg 1995; 113: 110-9. 3 Dhiwakar M, Thakar A, Bahadur S, Sarkar C,Banerji U, Handa KK,Chabra SK — Preoperative diagnosis of allergic fungal sinusitis. Laryngoscope 2003; 113: 688-94. 4 Marple BF — Allergic Fungal Rhinosinusitis. Current theories and management strategies. Laryngoscope 2001; 111: 1006-19. 5 Torres C, El Naggar AK, Sim SK, Ayala AG — Allergic fungal sinusitis: a clinicopathological study of 16 cases. Human Pathol 1996; 27: 793-9. 6 Ravi kumar A, Mohanthy S, Vatsanath RP, Raghunandan S. Allergic Fungal Sinusitis- a clinicopathological study. Ind J Otolaryngol Head Neck Surg 2004; 56: 317-20. 7 Wicker GM — Pediatric allergic fungal sinusitis: another “great masquerade”. Paed Asthma Allergy Immunol 1993; 7: 147-56. 8 Goh BS, Gendeh BS, Rose IN, Pit S, Samad SA — Prevelence of allergic fungal sinusitis in refrectory chronic rhinosinusitis in adult Malaysian. Otolaryngol Head Neck Surg 2005; 133: 27-31. 9 Manning SC, Merkel M, Kriessel K, Vuitch F, Marple B — Computerised tomographic and magnetic resonance diagnoses of allergic fungal sinusitis. Laryngoscope 1997; 107: 170-6. 10 Bent J, Kuhn F — Diagnosis of Allergic Fungal Sinusitis. Otolaryngol Head Neck Surg 1994; 111: 580-8. 11 Dhiwakar M, Thakar A, Bahadur S, Sarkar C,Banerji U, Handa KK,Chabra SK — Preoperative diagnosis of allergic fungal sinusitis. Laryngoscope 2003; 113: 688-94. 12 Malm L — Assessment and staging of nasal polyposis. Acta (Continued on page 24)


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Observational Study

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METHODOLOGY

Effect of hypothyroidism on lipid profile of Type 2 diabetic patients Soham Mukherjee , Swati Shriwastava , Prakash Keswani , Shrikant Sharma , Ganesh Narain Saxena 1

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Diabetes mellitus & Hypothyroidism are two common endocrinopathies in adult population. Most studies reveal that in patients with Type 2 Diabetes mellitus prevalence of hypothyroidism is more than general population. The study is designed to find out relationship of lipid profile in patient with hypothyroidism & euthyroid patients in the study group with Type 2 Diabetes mellitus. 101 patients with Type 2 Diabetes Mellitus with hypothyroidism & 203 patients with Type 2 Diabetes Mellitus without thyroid dysfunction of both sex & age >40 year from various medical wards & OPD were considered for study. Those who used medications that can affect thyroid function and lipid profile were excluded from the study. Fasting lipid profile was measured in this group. It was found that there was significant difference exists between euthyroid & hypothyroid groups in respect to LDL (Euthyroid-110.28 ± 35.27, Hypothyroid129.72 ± 35.68; p value <0.001) & TG (Euthyroid- 199.08 ± 49.58, Hypothyroid-215.13 ± 51.04; p value <0.01) level with higher value in hypothyroid group. No significant difference exists in regard to HDL value (Euthyroid- 41.86 ± 15.67, Hypothyroid-41.43 ± 17.69; p value >0.05). Hypothyroidism can aggravate dyslipidemia in type 2 Diabetes & thus increases atherogenic risk. [J Indian Med Assoc 2017; 115: 22-4]

Key words : Type 2 diabetes mellitus, Hypothyroidism, HDL, LDL.

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iabetes mellitus & thyroid dysfunctions are two common endocrinopathies in adult population. Most studies reveal that in patients with Type 2 Diabetes mellitus prevalence of thyroid dysfunctions is more than general population . While others have the opinion that prevalence of thyroid dysfunctions is similar in Type 2 Diabetes mellitus patients as in general population . Both Type 2 Diabetes mellitus & hypothyroidism have been found to be associated with dyslipidemia & atherosclerosis & thus both may have causative relation with macrovascular complications in patients with Type 2 Diabetes mellitus (Hypertension, IHD and PVD). Diabetic dyslipidemia is characterised by: high triglyceride concentrations, low high density lipoprotein-cholesterol (HDL-c) concentrations and normal low density lipoprotein-cholesterol (LDL-c) concentrations, but LDL particles are small and dense. It is well known that alterations in thyroid function result in changes in the composition and transport of lipoproteins . In general, overt and subclinical hypothyroidism is associated with hypercholesterolemia mainly due to elevation of low density lipoprotein (LDL) 1

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Department of Medicine, SMS Medical College, Jaipur 302004 1 MD, 3rd year Resident 2 MD (Gen Med), Associate Professor 3 MD (Gen Med), DM (Endocrinology), Professor 4 MD (Gen Med), Assistant Professor 5 MD (Gen Med) Professor

cholesterol levels, whereas high density lipoprotein (HDL) cholesterol concentration is usually normal or even elevated . The study is designed to find out relationship of lipid profile in patient with hypothyroidism & euthyroid patients in the study group with Type 2 Diabetes mellitus. 4

MATERIALS AND METHODS

Study type & design - Hospital based comparative study. Study place - SMS Hospital. Medicine wards & medical OPD Group 1 - 101 patients with Type 2 Diabetes mellitus with hypothyroidism Group 2 - 203 patients with Type 2 Diabetes mellitus with normal thyroid functions. Inclusion criteria : Patients with type 2 diabetes mellitus in the age group of 40-80 year were included in the study. (1) Age >40 year. (2) Patients with type 2 diabetes mellitus with hypothyroidism. (3) Patients with type 2 diabetes mellitus without thyroid dysfunction. Exclusion criteria : (1) Age < 40 year. (2) Seriously ill patients. (3) Patients on life supporting measures. (4) Those unable to give informed consent. (5) Diabetes mellitus other than type 2 ie, secondary, type1, diabetes with pregnancy, acute infection. (6) Those who used medications that can affect thyroid function. (7) Patients on steroid and lipid lowering agent.

Selected patients were evaluated clinically by history taking including age, sex, socioeconomic status, duration of diabetes and clinical examination, including general physical examination, assessment of vitals & systemic examination. Anthropometric parameters (weight, height, BMI, waist circumference, hip circumference, waist hip ratio) were obtained by using standard techniques . Blood investigations such as fasting blood sugar, post prandial blood sugar, urea, creatinine, electrolytes, bilirubin, SGOT, SGPT, HbA1C, total lipid profile, including HDL, LDL, and triglyceride were measured according to standard techniques . All reference values were taken from ADA guideline & Harrisons Principle of Medicine . Statistical analysis was done by chi squire test and Z test. 5

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Fig 1 — Showing graph of Hypothyroid and Euthyroid Table 1 — Clinical and Laboratory Characteristics of Diabetic Patients Type 2 diabetes with hypothyroidism 64.60 ± 8.35 28 (27.72) 73(72.28)

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OBSERVATIONS

There was no significant difference between the two groups in respect to age, duration and positive family history of diabetes. We have observed that in hypothyroidism group, females were disproportionately larger in number (72.28%) as compared to the group with normal thyroid function (49.26%). A significant difference also exists between the two groups in respect to BMI (30.41 ± 4.90 in euthyroid diabetic patients and 31.76 ± 5.04 in hypothyroid diabetic patients). In our study we have found significant difference between the two groups in respect to their lipid profile. We have observed highly significant difference between the two groups in respect to LDL cholesterol (Euthyroid110.28 ± 35.27, Hypothyroid-129.72 ± 35.68; p value <0.001) with higher values in hypothyroid patients. We have also found significant difference in respect to triglyceride (Euthyroid- 199.08 ± 49.58, Hypothyroid215.13 ± 51.04; p value <0.01). This values were also higher in hypothyroid diabetic patients as compared to euthyroid diabetics. Though mean HDL value was found to be higher in euthyroid group but the difference is statistically non significant (Euthyroid- 41.86 ± 15.67, Hypothyroid-41.43 ± 17.69; p value >0.05). We have observed that HbA1c value was significantly higher in type 2 diabetes with hypothyroidism (9.94 ± 2.00) than euthyroid diabetes (8.51 ± 1.46). We have also found significant difference between the two groups in regard to nephropathy. But no significant relationship was observed between presence of hypothyroidism with other microvascular and macro vascular complications of diabetes (Fig 1 & Table 1). DISCUSSION

In our study LDL cholesterol and triglyceride was found to be significantly higher in hypothyroid diabetic groups as compared to euthyroid diabetic group. Though

Age (in years) Sex Male Female Duration of diabetes (in years) 10.86 ± 5.73 Family history of diabetes 25 (24.75) BMI (kg/mt ) 31.76 ± 5.04 Hemoglobin (gm/dl) 10.66 ± 1.71 Creatinine (mg/dl) 1.22 ± 0.28 HbA1c 9.94 ± 2.00 8.51 ± 1.46 LDL cholesterol 129.72 ± 35.68 HDL cholesterol 41.43 ± 17.69 Triglyeride 215.13 ± 51.04 Retinopathy 33 (32.67) Neuropathy 32 (31.68) Nephropathy 29 (28.71) CAD 21 (20.79) 34 (16.75) HTN 44 (43.56) 96 (47.29) 2

Type 2 diabetes P value with normal thyroid function 64.53 ± 8.07 > 0.05 103 (50.74) < 0.001 100 (49.26) 10.64 ± 5.24 53 (26.11) 30.41 ± 4.90 10.96 ± 2.04 1.21 ± 0.24 < 0.001 110.28 ± 35.27 41.86 ± 15.67 199.08 ± 49.58 69 (33.99) 63 (31.03) 26 (12.81) > 0.05 > 0.05

> 0.05 > 0.05 < 0.05 > 0.05 > 0.05 < 0.001 > 0.05 < 0.01 >0.05 > 0.05 < 0.001

mean HDL value was found to be higher in euthyroid group but the difference is statistically non significant. Both Type 2 DM & hypothyroidism have been found to be associated with dyslipidemia & atherosclerosis . Mohammad Afkhami-Ardekani had found that there was a significant difference in regard to TG, LDL and HDL between diabetics patients with thyroid dysfunction and without thyroid dysfunction (P =0.001). Moreover serum lipids were significantly higher and HDL was lower in subjects with subclinical hypothyroidism compared with age and sex matched euthyroid subjects . Though we have found statistically significant higher lipid values in hypothyroid group but we did not observe any significant difference in respect to HDL value. Athanasia Papazafiropoulou, et al observed that patients with thyroid dysfunction had higher values of HDL-cholesterol levels (P = 0.01), and lower values of LDL-cholesterol levels (P =0.001) in comparison with patients without thyroid dysfunction. He also found significant associations between the presence of thyroid 8

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dysfunction and LDL-cholesterol levels and HDLcholesterol levels . JIN-KUI YANG et al, had observed significant differences between the type 2 diabetics with subclinical hypothyroidism and euthyroid diabetics in respect to LDL cholesterol. They also found that serum lipids were significantly higher and HDL was lower in subjects with subclinical hypothyroidism compared with age and sex matched euthyroid subjects . HS Chen et al, had found that type 2 diabetic patients with subclinical hypothyroidism did not differ from euthyroid diabetics with regard to age ,sex, type 2 diabetes duration, BMI, glycemic control and lipid profile . This finding is not consistent with our result. However we have considered both overt and subclinical hypothyroidism together in our study. Gray RS et al in his study had found that diabetics with primary thyroid failure, without overt clinical evidence of hypothyroidism, had a higher mean plasma cholesterol concentration than euthyroid diabetics of equivalent age, sex, weight, diabetic treatment and duration of diabetes. No significant difference in triglyceride concentration was observed between the two groups of diabetics. Thyroxine replacement therapy in 18 diabetics with subnormal T4 concentrations was associated with a reduction (p less 0.01) in mean plasma cholesterol concentration to 5.8 ± 0.3 nmol/L, but no significant change in triglyceride concentration . J Kvetny et al had found that Subclinical hypothyroidism was associated with higher concentrations of triglycerides . It has been shown, both in euthyroid non-diabetic and diabetic adults , that small variations in TSH at different levels of insulin sensitivity might exert a marked effect on lipid levels. The interaction between insulin resistance and lower thyroid function might be a key determinant for a more atherogenic lipid profile in these populations. Thus we conclude that hypothyroidism cause worsening of dyslipidemia in type 2 diabetes patients. Effect of thyroxine replacement on lipid profile in type 2 diabetes patients with hypothyroidism requires a further large clinical trial. 10

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REFERENCES 1 Radaideh AR, Nusier MK, Amari FL, Bateiha AE, El-Khateeb MS, Naser AS, Ajlouni KM — Thyroid dysfunction in patients with type 2 diabetes mellitus in Jordan. Saudi Med J 2004; 25: 1046-50. 2 Gabriela Brenta. Diabetes and Thyroid Disorders. British

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Journal of Diabetes and Vascular Disease 2010; 10: 172-7. 3 Gray RS, Smith AF, Clarke BF — Hypercholesterolemia in diabetics with clinically unrecognised primary thyroid failure. Horm Metab Res 1981; 13: 508-10. 4 Canaris GJ, Manowitz NR, Mayor G, Ridgway C — The Colorado thyroid disease prevalence study. Arch Intern Med 2000; 160: 526-34. 5 Dalton M, Cameron AJ, Zimmet PZ, Shaw JE, Jolley D, Dunstan DW, Welborn T A — Waist circumference, waist–hip ratio and body mass index and their correlation with cardiovascular disease risk factors in Australian adults. Journal of Internal Medicine 2003; 254: 555-63. 6 Nadia A, Jumah — Epidemiological, clinical & biochemical profile of type 2 diabetes in Kuwait. Bull Alex Fac Med 2009; 167-75. 7 Fauci AS, Braunwald E, Kasper DL, Hauser SL, Lngo DL, Jameson JL, Loscalzo J, editors — Harrisons principles of internal medicine. 17th ed. United states of Amerika: McGraw-Hill Companies; 2008. 8 Staub JJ, Althaus BU, Engler H, Ryff AS — Spectrum of subclinical and overt hypothyroidism: effect on thyrotropin, prolactin, and thyroid reserve, and metabolic impact on peripheral target tissues. Am J Med 1992; 92: 631-42. 9 Afkhami-Ardekani Mohammad, Rashidi Maryam, Shojaoddiny Ahmad. Effect of Thyroid Dysfunction on Metabolic Response in type2 Diabetic patients. Iranian Journal of Diabetes and Obesity 2010; 2: 20-6. 10 Papazafiropoulou A, Sotiropoulos A, Kokolaki A — Prevalence of Thyroid Dysfunction Among Greek Type 2 Diabetic Patients Attending an Outpatient Clinic. J Clin Med Res 2010; 2: 75-8 11 Jin-Kui Yang, Wei Liu, Jing Shi, Yi-Bing Li. An Association Between Subclinical Hypothyroidism and Sight-Threatening Diabetic Retinopathy in Type 2 Diabetic Patients. Diabetes Care 2010; 33: 1018-20. 12 Chen HS, Wu TEJ, Jap TS, Lu RA, Wang ML, Chen RL, Lin HD — Subclinical hypothyroidism is a risk factor for nephropathy and cardiovascular diseases in Type 2 diabetic patients. Diabetic Medicine 2007; 24: 1336-44. 13 Kvetny J, Heldgaard PE, Bladbjerg EM, Gram J — Subclinical hypothyroidism is associated with a low-grade inflammation, increased triglyceride levels and predicts cardiovascular disease in males below 50 years. Clinical Endocrinology 2004; 61: 232-8. 14 Bakker SJ, ter Maaten JC, Popp-Snijders C — The relationship between thyrotropin and low density lipoprotein cholesterol is modified by insulin sensitivity in healthy euthyroid subjects. J Clin Endocrinol Metab 2001; 86: 120611. 15 Chubb SA, Davis WA, Davis TM — Interactions among thyroid function, insulin sensitivity, and serum lipid concentrations: The Fremantle Diabetes Study. J Clin Endocrinol Metab 2005; 90: 5317-20.

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Otolaryngol (stoch) 1997; 117: 465-67. 13 Kupferberg SB, Bent JP, Kuhn FA — Prognosis for allergic fungal sinusitis. Otolaryngol Head Neck Surg 1997; 117: 3541. 14 Manning SC, Holman M — Further evidence for allergic pathophysiology in Allergic Fungal Sinusitis. Laryngoscope 1998; 108: 1485-96. 15 Rupa V, Jacob M, Mathew MS — Clinicopathological and mycological spectrum of allergic fungal sinusitis in south India. Mycoses 2002; 45: 364-7.

16 Shubert MS, Goetz DW — Evaluationand treatment of allergic fungal sinusitis. J Allergy Clin Immunol 1998; 102: 395-402. 17 Marple BF — Allergic Fungal Rhinosinusitis.Current theories and management strategies. Laryngoscope 2001; 111: 1006-19. 18 Denning DW,Van Wye JE, Lewistn NJ — Adjunctive treatment of allergic bronchopulmonary Aspergillosis with itraconazole. Chest 1991; 100: 813-9.

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Observational Study Placental blood drainage in the management of the third stage of labour Nirmala C1, Pandu D2, Dakshayini B R3 To evaluate and compare the placental blood drainage group and controlled cord traction group in the management of the third stage of labour. Two hundred low risk pregnant women admitted to labour ward with term gestation were randomly divided into two groups of 100 women each. In group I, after delivery of the baby, the umbilical cord was doubly clamped and cut and placenta delivered by controlled cord traction after signs of placental separation appeared. In group II, the umbilical cord was unclamped immediately after it was cut and left open to drain into a kidney tray. Both the groups were compared with respect to the duration of third stage of labour, amount of blood loss and rate of occurrence of retained placenta and post partum haemorrhage. Placental blood drainage group had a significant decrease in the duration of the third stage of labour (p<0.05) and blood loss (p<0.05) compared to controlled cord traction group. Reduction in packed cell volumes 24 hours post partum was significantly more in the controlled cord traction group compared to placental blood drainage group (p<0.05). Placental blood drainage in the third stage of labour is a safe, simple and non invasive method which can be advocated to prevent post partum haemorrhage. [J Indian Med Assoc 2017; 115: 25-7 & 32]

Key words : Post Partum haemorrhage, placental blood drainage, controlled cord traction.

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ostpartum haemorrhage (PPH) is one of the most com-mon causes of maternal deaths throughout the world. Pregnancy and childbirth involves significant health risks, even to women with no preexisting health problems. Worldwide there are an estimated 500,000-600,000 deaths of mothers during childbirth annually, of which 25% are due to severe bleeding. World Health Organization (WHO) also estimated 20 million annual maternal morbidities due to hemorrhage. In developing countries, where maternal mortality rates are exponentially higher, PPH plays an even greater role . Postpartum haemorrhage is defined as blood loss after childbirth in excess of 500ml. Anemia is one of the most common causes of maternal morbidity and mortality in our country. Even a small loss of blood can be of great significance in these anemic patients . Active management of third stage of labour, including early cord clamping and controlled cord traction and administration of oxytocic drugs such as ergometrine and oxytocin have been beneficial . The present study is undertaken to evaluate placental blood drainage during vaginal delivery as a method of shortening third stage of labour, reducing the blood loss and decreasing its associated complications (Figs 1&2). 1

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Department of Obstetrics and Gynaecology, JJM Medical College and Hospital, Davangere 577004 1 MBBS, MS (Obst & Gynae), Fellowship in Gynaeconcology 2 MBBS, MS (Gen Surg), MCH Oncosurgery, Associate professor of Surgical Oncology, Kempegowda Institute of Medical Sciences, Bangalore 560070 3 MBBS, MD (Obst & Gynae), DGO

METHODOLOGY

The present study was a randomized controlled study conducted in the department of Obstetrics and Gynaecology at the teaching hospitals attached to JJM Medical College, Davangere namely: (1) Chigateri General Hospital ( 2 ) Wo m e n a n d Children Hospital (3) Bapuji Hospital 200 pregnant women belonging to low risk group, admitted to labor ward from July 2005 to June 2007, were taken up for the study. Inclusion criteria: • All cases of normal singleton pregnancy with spontaneous onset of labour, live fetus, vertex presentation. •

Fig 1 — Duration of the third stage of labour

Fig 2—Blood loss in the third stage of labour

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Exclusion criteria : • Women who were given episiotomy • Multifetal pregnancy • Intrauterine death • Abnormal presentation (breech, hand, cord) • Previous history of cesarean section • Grand multipara • Chorioamnionitis • Antepartum haemorrhage • Fetal distress • Anemia in pregnancy • Pregnancy induced hypertension • Pregnancy with heart disease. These women were divided into two groups of 100 each by suitable random sampling technique. Methodology : An informed consent was taken from the patients who met the inclusion criteria. These women underwent a thorough general and systemic examination of cardiovascular system, respiratory system, obstetric examination and per vaginal examination. In Group I women, after delivery of the baby, the umbilical cord was doubly clamped and cut and placenta delivered by controlled cord traction after the signs of placental separation appeared. Injection Methyl ergometrine 0.2 mg was given iv after delivery of the placenta. In Group II women, the umbilical cord was unclamped immediately after it was cut and left open to drain into a kidney tray, until the flow ceased or signs of placental separation appeared, whichever was earlier. Following this, the placenta was delivered by controlled cord traction and Inj. Methyl ergometrine 0.2 mg was given i.v. after delivery of the placenta. The duration of the third stage was calculated using a stopwatch. The blood loss during the third stage of labour was calculated by using a PPH bag (Fig 3) placed beneath the buttocks of the patient. It is a modified ordinary thin (20 microns) plastic bag of 24" x 16" size with a self handle (ie, handle made from the same plastic sheet) as is commonly used by shop keepers. The handle serves two very important purposes, (i) It ensures that the bag clings to the body of the patient so that no blood can trickle up to the back of the patient and (ii) The bag is fixed high up and ensures that all the blood gravitates down to the bag proper. The right lower corner of the bag is calibrated at 50, 100, 200, 300 and 500 ml volume of blood which gives an instant measurement. The estimated total blood loss was noted. The need for initiation of intravenous fluids or blood transfusion was noted. If uterine bleeding was more than normal, additional oxytocics were given.

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which every obstetrician has to f a c e o f t e n unexpectedly. The incidence is between 3-6%. It continues to be a life threatening cause accounting for 25% - 30% of maternal deaths in the developing countries . Fig 4 — Changes in Haemoglobin levels The Brandt-Andrew Maneuver advocates awaiting the signs of placental separation followed by controlled cord traction and suprapubic pressure to assist expulsion of the placenta. Active management of the third stage of labour aims at producing Fig 5 — Changes in Packed cell volumes strong uterine contraction with a uterotonic agent at the time of birth to assist placental separation and expulsion. This method reduces the duration of the third stage of labour whilst concomitantly reducing the total blood loss occurring during the third stage of labour. Placental blood drainage is another method which could be advocated as a part of active management of the third stage labour . The difference in the mean duration of the third stage of labour (Table 1) between the two groups was 2.08 (p<0.005). Thus, placental blood drainage is an effective method to reduce the duration of the third stage of labour. The decrease in the size of the placenta on blood drainage may cause faster retraction of the placental site causing early separation. In a similar study by Nirmal Gulati et al, the mean val4

Fig 3 — Showing PPH Bag

In case of non-separation of placenta for more than 30 minutes, manual removal of placenta was done. The weight, sex and apgar score of the baby were noted. The placenta and membranes were inspected to ensure its expulsion in its entirety. The pulse rate, blood pressure and state of the uterus were noted immediately after delivery. The patients were kept under observation for the next hour for any complications. Packed cell volume (PCV)/hematocrit and haemoglobin (Hb) in gm% was done at the time of admission to the labour room and repeated 24 hours after d e l i v e r y b y Wi n t r o b e s m e t h o d a n d S a h l i ’s hemoglobinometer respectively (Figs 4&5). Statistical analysis of the two groups was done by one way Anova, Chi-square test (c ) test and z-test (normality test). Chi-square test was used to analyse categorical data and Z test for comparing mean of the two groups. A two tailed p < 0.05 was considered statistically significant. Analysis was done in SPSS software package. 2

RESULTS

The mean maternal age in years in group I and group II were 23.6 ± 3.2 and 23.8 ± 3.1 respectively (p = 0.68). Most of the women were multiparous in both the groups except one who was a primigravida. Comparison of the duration of third stage (Table 1) showed a significant decrease in the placental blood drainage group with p value of < 0.001 Inter-group comparison showed that the mean difference in the third stage blood loss (Table 2) was 18.9 ml with p value of < 0.001. Comparative evaluation of duration with blood loss of the third stage (Table 3) showed that more is the duration more was the blood loss. There was a relatively less decrease in haemoglobin and haematocrit values (Table 4) in the study group than in the control group (p<0.05). Additional oxytocics were needed in only 3% of the placental blood drainage group as compared to 8% of the control group. DISCUSSION

Post partum haemorrhage is an obstetric emergency

2

Table 1 — Comparison of the duration of the third stage

Mean ± SD Range

Control group (n = 100) 4.08 ± 1.25 2 – 10.00

Study group (n = 100) 2.00 ± 10.3 0.75 – 5.00

Control versus Study mean difference (min) 2.08

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ues of duration of the third stage of labour in the controlled cord traction group and placental blood drainage groups were 5.72 min and 2.94 min respectively (p<0.01) . In the present study, 52% and 87% of the cases had blood loss of <50 ml in the controlled cord traction group and in placental blood drainage group respectively. In the controlled cord traction group, 8% had blood loss of >81 ml but none in the placental blood drainage group .The mean difference in the third stage blood loss was 18.9 ml (p < 0.001), thus reducing the amount of blood loss significantly. In a similar study by Thomas IL et al, it was concluded that placental drainage of cord blood confers no extra benefits . According to Shravage JC et al, the average third stage blood loss was 175 ml and 252 ml in the study and control groups respectively (P < 0.001) . Comparative evaluation showed that there was a linear relationship between the duration of the third stage of labour and the amount of blood lost (Table 3). In the present study, intergroup comparison of hemoglobin changes (Table 4) shows that there was an insignificant reduction of postpartum haemoglobin in both the groups. This could be explained by the inaccuracy of the parameter in showing the blood loss. In a randomised controlled trial conducted by David Chelmow et al, it was found that controlled cord traction group plus immediate cord drainage significantly reduced the drop in haemoglobin compared with expectant management [median haemoglobin drop : 0.95 g/dl with controlled cord traction group with drainage vs 1.40 g/ dl with expectant management (p = 0.0002)] . Hematocrit is a reliable measurement of total red cell mass and a sensitive indicator of acute blood loss compared to haemoglobin. Thus there was a significant reduction of hematocrit (p<0.05) in each group following delivery with less reduction in the study group (Table 4). 5

6

7

8

Table 3 — Comparison of duration with blood loss Duration Control group of III stage No of Range Mean±SD (min) cases (< 5 min) 1-4 min (> 5 min) 6-10 min Total

Study group No of Range Mean±SD cases

62

36-114 49.2±12.7

95

20-68 35.2±11.3

38 100

34-120 65.7±17.6 34-120 55.5±16.7

5 100

48-80 63.2±11.4 20-80 36.6±12.8

Z = 12.9, p < 0.001 Table 4 — Comparison of hemoglobin and hematocrit changes Table 2 — Comparison of blood loss of the third stage

Mean ± SD Range

Control group (n = 100)

Study group (n = 100)

Control versus Study Mean difference (ml)

55.5 ± 16.7 34 – 120

36.6 ± 12.8 20 – 80

18.9

Z = 8.95, p < 0.001

Before delivery

After Difference delivery

Hemoglobin (g%) Z = 1.08, p = 0.28

Control group 10.4±0.8 Study group 10.3±0.7

9.7±0.8 9.9±0.7

0.7±0.2 0.6±0.9

Hematocrit (cmm) Z = 2.82, p < 0.05

Control group 31.1±2.3 29.6±2.3 Study group 30.9±2.1 29.7±2.1

1.5±0.8 1.2±0.7

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Observational Study Role of otorhinolaryngologist in management of head trauma with fracture temporal bone — our experience 1

M Venugopal , Sreeram P

2

Head trauma is one of the major causes of morbidity and mortality in our society. Many young adults are now injured and died following accidents. Temporal bone fractures form one of the most pronounced injuries following head trauma. To evaluate outcome of fracture temporal bone in head trauma by studying type of fracture, the proportion of subjects with hearing loss, associated traumatic facial nerve palsy and their prognosis. This is a descriptive study of cases of fracture temporal bone attended in the casualty of Government Medical College, Thiruvananthapuram, which are evaluated clinically as well as radiologically. Study period is 2 years. Major cause for fracture temporal bone was head trauma due to road traffic accidents. Majority of the subjects involved were young adults (20 - 40 years). Most common presentation to otolaryngologist was hearing impairment which often remains unnoticed. In most of the cases ear symptoms were recovered by early intervention. [J Indian Med Assoc 2017; 115: 28-9 & 32]

Key words : Temporal bone, hearing loss, HRCT temporal bone, facial nerve palsy.

T

rauma generally is a major cause of morbidity and mor-tality in any society. Cases of head trauma attending surgical casualty can be associated with temporal bone fracture. Unless there is clinical evidence of facial palsy or bleeding from ear, fracture temporal bone often remains unnoticed. They are most often detected when patients are evaluated for head injury with imaging or when complaints of hearing loss after recovering from head injury. One of the most important problems which remain unnoticed is hearing impairment. Similarly post traumatic facial nerve palsy may be noticed immediately or late. Posttraumatic hearing loss and facial palsy can have profound impact on individual’s emotional, physical and social well being. Most common cause of trauma is road traffic accident due to increase in number of vehicles. Though there are many studies on western literature regarding fracture temporal bone, the present study is to highlight role of otorhinolaryngologist in those patients with clinically and radiologically proved temporal bone fracture, so that we can reduce the functional impairment by early detection and treatment. Aim of the study : To evaluate outcome of fracture temporal bone in head trauma by studying the proportion of subjects with hearing loss, the type and degree of hearing loss along with the associated traumatic facial nerve palsy and their prognosis. Materials and methods : Descriptive study. Study period : 2 years. Inclusion criteria : Patients above 12 years of age either gender presenting with radiological evidence of D e p a r t m e n t o f E N T, G o v e r n m e n t M e d i c a l C o l l e g e , Thiruvananthapuram 695011 1 MS (ENT), DLO, DNB (ENT), Additional Professor 2 MBBS, MS (ENT), Resident

fracture temporal bone in head trauma .All the cases were confirmed by high resolution computerised tomographic (HRCT) scanning of temporal bone. Exclusion criteria : • Patient with congenital craniofacial anomalies • Patient with previous otological disease • Patients not willing to participate in the study and those who lost follow up. • Patients under 12 years were excluded due to logistic reason (as they attend pediatric surgery casualty). Patient included in the study were those attending surgical and ENT casualty of Govt. Medical College, Thiruvananthapuram, a tertiary care centre during the period march 2012 to February 2014. After getting informed consent each patients were clinically, radiologically and audiologically evaluated as per the profoma prepared. HRCT scan temporal bone was taken to know the type of fracture (longitudinal, transverse and oblique/mixed), to rule out bony fragments in facial canal and ossicular involvement. Follow up audiogram and facial nerve monitoring done in indicated cases. Other necessary investigations also have been done. The data collected is subjected to suitable statistical analysis including percentage analysis and graphical analysis. RESULTS

We studied 75 patients with age more than 12 years during the period of 2 years. Analysis of age distribution shows that maximum cases were reported between age group 31-40 years, followed by 20 -30 years as shown in the column chart (Fig 1). Out of 75 cases 84 % were males (Fig 2) and most common cause was road traffic accident (79 %). Common presentation was hearing impairment (72%) followed by bleeding from ear, vertigo and facial palsy.

Otoscopic examination showed evidence of haemotympanum in 21% of cases. HRCT scan temporal bone showed longitudinal fracture in 56% of case as shown in the Table 1. Regarding hearing loss, conductive hearing loss was noticed in 41% of cases, of which tympanogram in 62% shows type B curve indicating Fig 1 — Showing Age Distribution haemoty-mpanum and 15% showed type Ad curve. Sensory neural hearing loss noted in 16% followed by mixed hearing loss in 15%. Type of hearing loss is shown in Table 2. Degree of Fig 2 — Showing Sex Distribution hearing loss shows mild to moderate hearing impairment in majority of cases. Prognosis of hearing loss assessed by pure tone audiometry and shows improvement of hearing in 72 % of cases with proper treatment. Considering facial nerve palsy, 35% of mixed and 30% of transverse fracture had facial nerve palsy as illustrated in the Table 3. Out of 18 cases of facial nerve palsy 15 cases were delayed onset which recovered completely within 6 months by medical treatment. Out of 3 cases of immediate facial palsy without any evidence of bony fragment in the facial canal, 2 cases recovered completely. Cerebrospinal fluid (CSF) otorrhoea was more c o m m o n i n transverse fracture Table 1 — Distribution of cases according of temporal bone. to type of fracture All the cases of Type of fracture No of cases Percentage C S F o t o r r h o e a Longitudinal 42 56 10 13 r e c o v e r e d b y Transverse 23 31 c o n s e r v a t i v e Oblique/mixed Total 75 100 management. Persiste nt vertigo Table 2 — Distribution of cases according to the assessment of hearing noted in 2 No of cases Percentage cases out of Type of hearing loss 31 41 16 cases. Conductive hearing loss 12 16 Out of 8 Sensory neural hearing loss Mixed hearing loss 11 15 cases with No hearing loss 21 28 t i n n i t u s , Total 75 100 persistent symptom noted in one case. DISCUSSION

Radiologically proved case of temporal bone fracture presented in the surgical casualty of Govt.Medical Col

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l e g e , Table 3 — Distribution of facial nerve palsy with respect to the type of temporal bone fracture Thiruvanant h a p u r a m Type of fracture No of No of Percentage cases palsy facial with history 42 7 17 o f h e a d Longitudinal Transverse 10 3 30 trauma were Mixed/ oblique 23 8 35 studied in Total 75 18 24 detail. Study shows that majority of cases were between age group 20-40 years. Males were involved more (84%). Common cause was due to road traffic accident (79%). It is comparable with other studies like Freedom Johnson, Maroun T Semaan, Cliff A Megerian . This could be due to the fact that males are involved in rash driving and alcoholic intoxication. In our study 72 % had hearing impairment and 60% had ear bleeding. Hearing impairment may range from mild to profound as in Brodie HA, Thomson TC study. In another study by Debora P Wilson in1997 was 71% which is comparable to our study. HRCT temporal bone is the key radiological investigation in all the studies (Cannon CR, Jahrsdoerfer RA ). Fracture temporal bone can be classified in to longitudinal, transverse and oblique type depending on relation of the fracture line to long axis of petrous temporal bone. Ghorayeb BY and Yeakley described oblique fracture for more accurate description of three dimensional anatomy of fracture plane based on geometry of fracture. Even though there is another classification of fracture temporal bone by Kelly and Tami as otic capsule - sparing and otic capsule- violating, we followed the classification of longitudinal, transverse and oblique fracture. Longitudinal fracture was the most common in our study. Ghorayeb BY and Yeakly observed 75% oblique fracture. Hearing evaluation by audiometry showed 41% conductive hearing loss and was mainly due to haemotympanum as demonstrated by tympanometry. All these cases recovered by medical treatment. 15% of cases showed mixed hearing loss. Study by Freedom Johnson, Maroun T Semaan also reported conductive hearing loss was most common type followed by mixed hearing loss. Facial nerve palsy was noted in 30% of transverse fracture as compared with other studies. Out of 18 cases of facial palsy 15 cases were delayed onset, which recovered completely by conservative management with high dose of corticosteroid as in Brodie HA, Thompson TC series. There were 3 cases of immediate facial palsy. Out of which 2 recovered completely and one case there was no recovery even though there was no bony fragment in the facial canal and patient was not willing for facial nerve decompression. We should examine for facial nerve palsy in case of head injury. In the present study CSF otorrhoea was detected in a total of 5 cases. All the cases spontaneously resolved within 3 months. The incidence of CSF leak in patients with temporal bone fracture in series of Nosan DK, Benecke Jr, Murr AH is 11% with 1

2

3

4

5

1

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Observational Study

the ureter draining the upper pelvis of the left kidney crossed the ureter draining the lower pelvis of the same side (Fig 1 & 2). According to Dodson I , the duplication may be complete when the two ureters grow independently from the wolffian duct or incomplete when a single ureter divides, forming a bifid ureter before joining the kidney. Thus the Present study showed that the double ureters from both kidneys were not bifid and they represented the example of complete duplication (Fig 3). According to Dodson I , also stated that, where there is complete duplication, the ureter draining upper pelvis enters the bladder below the orifice of the ureter draining the lower pelvis of the kidney and although such duplicated ureters and kidneys often function normally, the caliber of one or both ureters may be smaller than normal and congenital strictures and ureteroceles are encountered more frequently than in single ureters. But the Present study showed that the double ureters on both the sides were completely duplicated from their commencement till their termination in the bladder as

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2

Double ureter : an important landmark in the field of dissection 1

2

M M Patel , T C Singel

The incidence of double ureter present bilaterally draws the utmost attention of any Doctor and as the occurrence of double ureter present on both sides and having complete course from both the kidneys makes it more interesting. During routine dissection procedure being carried out in the Anatomy department, the present study observed the important landmark of double ureter present bilaterally in one cadaver out of fifty four (54) cadavers dissected over a period of three years. Hence further cleaning and related dissected work was done and photographed and the discussion was carried out in comparison with various research workers. [J Indian Med Assoc 2017; 115: 30-2]

Key words : Double ureter, Dissection.

A

ccording to JC Ainsworth-Davis , a double ureter is always associated with a bifid renal pelvis. The duplication may be complete or incomplete. Dodson I had stated that such duplicated ureters and kidneys often function normally. Campbell MF , had mentioned that ureteral reduplication, so called double ureter may be incomplete or complete. Hamilton WJ , stated that the pelvis of ureter may lie mainly outside the renal hilus and the ureter may be duplicated on one or both sides for part or whole of its course and anomalies of this kind are present in 3 percent of cases. According to Romanes GJ , the ureter is sometimes duplicated in its upper portion and in rarer cases it is double throughout the greater part of its extent, or even in its whole length with two openings into the bladder. According to Herbut PA , unilateral duplication was quite common, while bilateral complete duplication was rare. Thus as it is a very rare phenomenon, the present study was undertaken to observe the cases of bilateral double ureter found in routine dissection procedure. 1

2

3

4

5

6

MATERIALS AND METHOD

In a routine dissection procedure in the Department of Anatomy, the incidence of double ureter was observed in one cadaver out of fifty four cadavers dissected (over a period of three years). The double ureters were photographed after clearing the field of dissection and they were present bilaterally. The age and sex of cadaver in which the double ureter was observed was male aged 60 years. OBSERVATION

The present case (cadaver in which double ureter was Department of Anatomy, M P Shah Medical College, Jamnagar, Gujarat 361008 1 MBBS, MS (Anatomy) Associate Professor 2 MBBS, MS (Anatomy) Professor & Head

found) showed the following observation. The photographs showed the presence of double ureters present in both the kidneys. The double ureters that were present in the cadaver were cleared for the proper view after superficial dissection of the structures covering them. The double reters showed that their commencement was independent and that they were not fifid, ie, they had separated origins from both the kidneys and they represented the complete duplication on both sides. The double ureters on both the sides were completely duplicated and devoid of any strictures. The termination of double ureters on both the sides was in the bladder through different openings. On the left side the ureter draining the upper pelvis crossed the uerter draining the lower pelvis.

2

6

pointed out in observation and that their caliber showed normal dimensions without the presence of strictures or ureteroceles present along them. Campbell MF , has suggested an important point that, the condition of ureteral reduplication is found unilaterally six times as often as bilaterally and, in, one in five cases the bilateral involvement is mixed with complete reduplication on one side and incomplete division on the other. On the contrary, present study showed the double ureters present bilaterally and with complete duplication of the ureters. The present study did not observe any incomplete duplication on any side. Even, Hamilton WJ , had mentioned an important point that anomalies of duplicated ureters are present in three percent of cases and rarely the ureter is greatly constricted, either at the junction of the pelvis with the tubular portion, or at the point where ureteric orifice opens into the bladder. The present study also noted the occurrence of double ureter in two percent of the cases (one case per fifty cadavers) and the junction of the pelvis with tubular portion was not constricted. According to Romanes GJ , it is a rarer case where in the ureter is double throughout the greater part of its extent, or even in its whole length with two openings into the bladder. Thus the present study had found a very rare case of double ureters present bilaterally throughout the length from its commencement till its termination. Therefore, the incidence of double ureter can be detected by various special investigations like MR urography, CT urography and intravenous pyelography in urology and various abdomino-pelvic surgeries. Henceforth, the surgeon while approaching the region should have prior knowledge about the course of double ureter in order to minimize the complications. 3

4

DISCUSSION

The empryological bases for the explanation of double ureters according to Herbut PA is, if there is premature or exaggerated cleavage of the tip of the ureteral bud an incomplete double ureter and double pelvis will result, or if a separate bud arises from the lower end of the wolffian duct, a complete double ureter and double pelvis will result. According to JC Ainsworth-Davis , a double ureter is always associated with bifid renal pelvis and the duplication may be complete or incomplete. In complete duplication two ureteric orifices are present on one side of the bladder and the ureter draining the upper pelvis of the kidney usually crosses the one which drains the lower pelvis and opens on to the trigone at a lower level. He also specified that incomplete duplication also implies two pelves, each having its own ureter and after a variable distance, however, these two ureters unite to form a single tube which opens into the bladder in the normal situation. The Present study showed the presence of double ureter on both the sides, where according to the photographs

Fig 3 — The above photograph shows that both the kidneys have been lifted up in the hands and the green arrows bilaterally and very clearly showing the double ureters

Fig 1 — The above photograph shows the green arrows on both the sides pointing to the double ureters present bilaterally; and the black arrows pointing to the kidneys

1

Fig 2 — The above photograph shows the green arrows pointing to the double ureters bilaterally and black arrows pointing to the kidneys

5

REFERENCES 1 Ainsworth-Davis JC — Essentials of urology. In section III Diseases of ureter. Blackwell scientific publications Oxford England 1950; 304 & 305. 2 Beer E, Mencher WH — Heminephroectomy in disease of the


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double kidney : Report of fourteen cases. Ann Surg 1938; 108: 705. 3 Campbell MF — Principles of Urology. In chapter 6, Embryology & anomalies of the urogenital tract. WB Saunders company. Philadelphia & London 1957; 146-7 & 148. 4 Dodson I — Urological surgery by Austin. In Chap. XIX congenital anomalies of the ureter & their treatment. III edition. Published by CV Morby company. 1956, 376.

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5 Hamilton WJ — Textbook of human anatomy. In urogenital system (ureters). II edition. Published by The Macmillan press Ltd. London & Basingstoke 1976; 423. 6 Herbut PA — Urological pathology. In chapter (IV) ureters & pelves. Lea & Febiger. Philadelphia 1952; I: 353-9. 7 Romanes GJ — Cunningham’s textbook of anatomy. In the urogenital system (the urinary organs). 11th edition. London Oxford university press 1972; 514.

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Case Report Cytodiagnosis of abdominal wall granular cell tumour — an uncommon tumour at a rare site Madhurima Mitra1

(Continued from page 27)

The reduced need for additional oxytocics in the placental blood drainage (3%) group shows its efficacy in effectively contracting and retracting the uterus. There were certain limitations of this study. Firstly, the observer could not be blinded regarding the two methods of delivering the placenta. This may have biased the calculation of the duration of the third stage of labour. Secondly, measuring blood loss by collecting in a PPH bag and hemoglobin by Sahli’s method compared to calorimetric method is inaccurate. Thus, the exact amount of blood loss might have been under estimated. Separation of normally inserted placenta is apparently achieved by mechanical factors. The completeness with which the placenta is separated is determined both by how much of the sub placental area of uterine wall is reduced as well as by the speed with which this is accomplished. A larger residue of blood in the placenta might interfere with this mechanism to some extent when separation occurs after delivery. CONCLUSION

Placental drainage of blood via the umbilical cord is a safe, simple and non invasive method. It results in reduced

third stage blood loss and reduction in duration of the third stage of labour without any increase in the complications. REFERENCES 1 Dildy GA — Post partum haemorrhage: New management option. Clin Obstet Gynecol 2002; 45: 330-44. 2 Arulkumaran S — The management of postpartum Haemorrhage. The management of labour, 1st Ed. Chennai, Orient Longman 1997; 183-96. 3 WHO 2001 — Global estimates of maternal mortality for 1995: Results of an in-depth review analysis and estimation strategy. Geneva: WHO; 2001. 4 Donald I — Post partum haemorrhage. Practical Obstetric problems, 5th Edn, New Delhi, BI Publications 1998; 74894. 5 Gulati N, Chauhan MB, Rana M — Placental blood drainage in management of third stage of labor of labor. J Obstet Gynaecol India 2001; 51: 46-8. 6 Thomas IL — Does cord drainage of placental blood facilitate delivery of the placenta? Aust NZ J Obstet Gynaecol 1990; 30: 314-5. 7 Shravage JC, Silpa P — Randomized controlled trial of placental blood drainage for the prevention of PPH. J Obstet Gynecol 2007; 57: 213-5. 8 Chelmow D — PPH: prevention. (1.2.07). Available from http://www.clinical/evidence/com/ceweb/conditions/pac/14 10/1410.13.jsp

(Continued from page 29)

spontaneous resolution in 95 to 100% cases. In otic capsule- violating fracture there is increased risk of CSF otorrhoea and facial nerve palsy in other studies. Vertigo found in 12% of cases which recovered by 3 to 6 months. Fracture temporal bone is common in head trauma. Early detection and prompt management is required for co-existing fracture temporal bone in patients with head injury. Early conservative management is recommended for hearing loss, CSF leak and facial palsy. Long term follow up is necessary to address these complications. CONCLUSION

In the present study of fracture temporal bone in patients with head trauma, findings were concluded as maximum number of cases were between the ages 20-40 yrs. Most of the cases were following road traffic accident. Males were involved more than females. Common presentation noted in fracture temporal bone was hearing loss. In our study, all the cases of delayed onset facial palsy and few cases of immediate facial palsy recovered completely with medical treatment. C.S.F. otorrhoea due to fracture temporal bone recovered completely without any sequelae following medical treatment. To conclude we suggest, as the major cause of

morbidity due to temporal bone fracture is road traffic accident, abiding strict road traffic rules may avoid our countrymen from the subsequent sufferings due to RTA. Early diagnosis, prompt treatment and follow up are needed to manage the cases of fracture temporal bone to reduce morbidity. REFERENCES 1 Freedom Johnson, Maroun T Semaan, Cliff A Megerian — Temporal bone fracture evaluation and management in modern Era. Otorhinolaryngology clinics of North America 2008; 41: 597-618. 2 Brodie HA, Thomson TC — Management of complications from 820 temporal bone fracture. Am J Otol 1997; 18: 18897. 3 Cannon CR, Jahrsdoerfer RA, Robert A — Temporal bone fractures. Review of 90 cases. Arch Otoraryngol 1983; 109: 285-8. 4 Ghorayeb BY, Yeakley JW — Temporal bone fracture: longitudinal or oblique? The case for oblique temporal bone fractures. Laryngoscope 1992; 102: 129-34 5 Kelly KE, Tami TA — Temporal bone and skull trauma .In Jackler RK, Brackmann DE, editor: Neurotology; Mosby St Louis 1994; 340-60. 6 Nosan DK, Benecke Jr, Jr JE Murr AH — Current perspective on temporal bone trauma. CSF Otolaryngol Head Neck Surg 1997; 117: 67-71.

Granular cell tumors are uncommon tumors of neural origin. Although any site could be involved, origin within the skeletal muscle is rare. Most reports on cytologic features of granular cell tumors so far, are from lesions at sites other than skin and soft tissue. A case of 43-year-old lady presented with anterior abdominal wall lump arising from rectus abdominis muscle of 6-7 months’ duration. CT guided FNA showed sheets and clusters of oval to polygonal tumour cells with dense granular cytoplasm and bland nuclear morphology. So possibility of benign granular cell tumor was suggested based on FNA smears. No material was available for cell block. Histopathological examination and S-100 stain of sections from excised mass confirmed the diagnosis on FNAC. Thus the cytopathologic features of granular cell tumours at rare sites like the skeletal muscle could also be distinctive enough to allow a correct diagnosis. [J Indian Med Assoc 2017; 115: 33 & 36]

Key words : Granular cell tumor, skeletal muscle, rectus abdominis, cytopathology, S-100.

G

ranular cell tumors are generally uncommon benign soft tis-sue neoplasms of controversial histogenesis . These distinctly rare lesions are believed to be of neural origin with skin and oral cavity being relatively common sites of involvement, although they can occur in any part of the body . However, origin of true granular cell tumors within the skeletal muscle and tendon sheath is rather rare . Granularity of tumor cells may be due to secondary lysosomes in the cytoplasm. This is a non-specific change that can be seen in many non-neural tumors such as those arising from smooth muscle, connective tissue, neuroglia, endothelial and epithelial cells. They are not true granular cell tumors and need to be differentiated from granular cell tumors of neural origin. This differentiation is done by S-100, specific immunohistochemical marker which is positive in granular cell tumours of neural origin alone . Most granular cell tumours are benign unless they exhibit definitive features of malignancy or recur or metastasise . Benign granular cell tumors are mostly within 2-3 cm in size and seldom more than 3 cm . Reports of cytopathologic diagnosis of granular cell tumors at rare sites like the muscle and tendon sheaths are found infrequently in literature . Here a case of a lady is reported who presented with a granular cell tumour over the rectus abdominis muscle and small portion of anterior rectus sheath, diagnosed initially on CT guided FNAC as granular cell tumour and later confirmed on histopathologic examination and on immunohistochemistry. 1

2,3

4

4

5

4,5

6

CASE REPORT

A 43-year-old lady presented with a lump of 6-7 months’ duration in the right lumbar area, which was occasionally painful. The patient had gastro-intestinal symptoms of incomplete evacuation and gastrointestinal reflux disease. Examination — The lesion was firm to hard, non-tender, mobile with no local rise of temperature. Clinically the mass appeared to be within the substance of the rectus abdominis muscle with some 1 MBBS, MD, DNB (Pathol), Assisstant Professor of Pathology, KPC Medical College and Hospital, Kolkata 700032

loose adhesions to a small portion of the anterior rectus sheath. A diagnosis of desmoid tumour of the anterior abdominal wall was made. Investigations — Radiological investigations in the form of USG, CT and MRI were done. CT scan of abdomen showed a rounded well enhancing, well defined anterior abdominal wall lesion suggestive of a desmoid tumour. USG showed a solid space occupying lesion of the right rectus abdominis muscle located distally. Although the lesion was in contact with the peritoneum, yet no peritoneal reach was noted. Desmoid tumor and benign fibrotic tumour were the differential diagnosis suggested on MRI. A CT guided fine needle aspiration was done from the lesion and smears were made. The Diff-Quik stained smears showed neoplastic cells in abundance, some in syncitial clusters and others lying singly. Background showed some stripped nuclei. Cells within the clusters were arranged in a vague follicular pattern. Cytoplasms of the intact cells were abundant and relatively dense with prominent granularity and indistinct boundaries. Nuclei of these cells were small, round or ovoid, uniform with bland chromatin. Based on the cytomorphological findings the possibility of granular cell tumor was suggested. Management & Followup — No material was available for cell block preparation, therefore need for excision biopsy of the tumour was suggested for confirmation of the diagnosis. Pathology — The specimen of resected mass was received in our department with attached muscle and fat, total measuring 8 x 6 x 2 cms. The external surface of the tumour was inked to look for infiltration into the margins. On serial sectioning, the mass was globular being 4.5 cm in diameter, light tan with a homogeneous cut surface. Microscopic examination showed the tumor to be composed of large polygonal cells with eosinophilic granular cytoplasm and central nuclei. These tumour cells were seen to form small nests in between the muscle and fibrocollagenous tissue (Fig 1, H&E x 200). The neoplasm was located within the skeletal muscle. The surgical resection margins were found to be free of the tumour.


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Further periodic acid Schiff staining with diastase resistance showed tumour cell staining of mixed intensity. Immunohistochemi stry — The tumor cells interspersed between the muscle fibres and fibrocollagenous tissue showed intense staining and strong granular cytoplasmic positivity for S-100.

solitary, firm to hard lumps and grow in an infiltrative manner. Cut surfaces are pale white to yellow, solid fleshy in appearance . Malignant transformation in granular cell tumors is rare and occurs only in 2% cases. Malignant lesions are larger in size than the benign counterparts (usually more than 5 cm), show necrosis, rapid growth, presence of vascular invasion and metastasis . Necrosis, nuclear pleomorphism, spindling and increased mitotic activity could be pointers to malignancy on histopathology . Although reports on recurrences vary yet some apparently benign granular cell tumors are known to recur and metastasise . Local recurrence of granular cell tumour is associated with incomplete excision, therefore complete excision of tumour is important to prevent recurrences. Patient has to be evaluated at periodic intervals to rule out malignant transformation and late recurrences. 4

1,2

4

1-4

DISCUSSION

Granular cell tumors are uncommon although exact figures on their frequency of occurrence internationally are unavailable. Females are more commonly Fig 1 — Microphotograph Showing affected than males, Granular Cells in Nests between peak being between the Muscles and Collagenous Tissues fourth and the sixth decades . Moreover though granular cell tumors are known to occur at any site, origin within the skeletal muscle is rather rare . Majority of the granular cell tumors are benign and generally less than 3 cm in size. They are typically 2

4

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REFERENCES

1 Devi K, Mohanty P, Mohanty L, Bhuyan P — Cytodiagnosis of granular cell tumor: a case report. Indian J Pathol Microbiol 2007; 50: 61-2 2 Debabrata B, Sumit S, Jnan PB — Granular cell tumor on a vaccination scar in a young girl. Indian J Dermatol 2006; 51: 196-7. 3 Boulos R, Kathlyn MD, Phillippe DJM — Granular cells tumor of the palate : a case report. Am J Neuroradiol 2002; 23: 8504. 4 Vladimir O,Vinod BS, Ashwini WP, Nagarjun R — Granular cell tumours.http://www.emedicine .com/Med/topic 2493.htm. 5 Craig E, Rodriguez R,Ruben B — Granular cell tumor of the scrotum. Dermatol Online 2005; 11: 25 6 Mrinmay M, Dilip D — Fine needle aspiration cytology diagnosis of a cutaneous granular cell tumor in a 7 year old child: a case report. Acta Cytol 2001; 45: 263-6.

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