Journal april 2016 final by ejima

Dr S S Agarwal

Dr K K Aggarwal

Dr Debasish Mukherjee

Dr Santanu Sen

National President, IMA

Honorary Secretary General, IMA

Honorary Editor, JIMA

Honorary Secretary, JIMA

Volume 114

u Number

u Kolkata u April 2016

CONTENTS Editorial : u Diabetes : scale up prevention, strengthen care, and enhance surveillance — Debasish Mukherjee, Dalia Chatterjee..........................................................................................5 Originals and Papers : u Retinopathy of prematurity screening in a rural based hospital of central India — Kanav Gupta, Rekha Khandelwal, Shashank Bidaye, Mohana Majumdar ...................................7 u A Randomized study comparing efficacy and safety of milnacipran versus escitalopram on patients of major depressive disorder — Chanchal Kumar Dalai, , Tapas Jyoti Roy Gautam Bandyopadhyay, Shirsendu Mondal, Sayanti ghosh, Sushobhan Pramanik, Madhumita Ray ......................................................................12 Practitioners’ Series : u To study the effects of hyperbaric oxygen therapy in chronic diabetic foot lesions — G R Ekbote, Sharad K Waje, Pankaj Bhalerao ...............................................................................18 Preliminary Report : u Malaria infection and ABO blood groups : a study conducted in the central Indian state of Madhya Pradesh — Sherly T D, G Vyas ..................................................................................22 Current Topic : u Current and future trends in the management of thyroid associated ophthalmopathy — Garima Agrawal, D C Mehta ..............................................................................24 Case Notes : u A rare case of Kimura’s disease of cheek — Mukesh Mishra, Sandhya Joshi ......................................28 u Joubert syndrome : a case report — P A Fazal Ghafoor, Sajeer K T, Jamaludheen C V .......................30 u A rare case of leukaemoid reaction in Plasmodium falciparum infection : a case report — Ashutosh Kumar, Rashmi Kushwaha, Vimala Venkatesh, Mastan Singh ........................................31 u Bilateral non-arteritic anterior ischemic optic neuropathy (NAION) — a case report — Asha R Prasad, S P Jakhanwal ......................................................................................33 Supplement ................................................................................................................................................36 3

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Diabetes : scale up prevention, strengthen care, and enhance surveillance Dr Debasish Mukherjee

Dr Dalia Chatterjee

MBBS, DLO, MS Honorary Editor, JIMA

MBBS, DTM&H, MD Guest Editor

very year, the World Health Organization selects a priority area of global public health concern as the theme for World Health Day, which falls on 7 April, the birthday of the Organization.

IMA New Initiatives 1.

Editorial

The theme for World Health Day 2016 will be diabetes, a noncommunicable disease (NCD) directly impacting millions of people of globally, mostly in low- and middle-income countries. The prevalence of diabetes have been steadily increasing in the past few decades, in particular in low- and middleincome countries. Knowledge exists to reverse this trend through targeted prevention and appropriate care. But diabetes – the main forms of which are type 1 and type 2 diabetes – is not just a health issue. Diabetes and its complications bring about substantial economic loss to people with diabetes and their families, and to health systems and national economies through direct medical costs and loss of work and wages. Working to prevent, detect and treat diabetes is also critical to development. Within the 2030 Agenda for sustainable Development, Governments have set an ambitious target to reduce premature mortality from NCDs – including diabetes – by one third; achieve universal health coverage; and provide access to affordable essential medicines – all by 2030. Diabetes is one of four priority NCDs targeted by world leaders in the 2011 Political Declaration on the Prevention and Control of NCDs and the SDGs 2016-2030. The Global Action Plan for the Prevention and Control of NCDs 20132020 provides a roadmap and menu of policy options to attain nine voluntary global targets, including an additional target to halt the rise in diabetes and obesity by 2025. Diabetes, therefore, is an issue relevant to people around the world, as well as multiple stakeholders, including government, civil society, the private sector, and intergovernmental agencies. While every country and community is at a different stage in addressing its diabetes challenge, there are a number of activities that could be considered at national and local level on World Health Day 2016 to help achieve its objectives to increase awareness and trigger a set of actions to tackle diabetes. Diabetes is a chronic, metabolic disease characterized by elevated levels of blood glucose (or blood sugar), which leads over time to serious damage to the heart, blood vessels, eyes, kidneys, and nerves. The most common is type 2 diabetes, usually in adults, which occurs when the body becomes resistant to insulin or doesn't make enough insulin. In the past three decades the prevalence of type 2 diabetes has risen dramatically in countries of all income levels. Type 1 diabetes, is a chronic condition in which the pancreas produces little or no insulin by itself. For people living with diabetes, access to affordable treatment, including insulin, is critical to their survival. There is a globally agreed target to halt the rise in diabetes and obesity by 2025. The mission of the WHO Diabetes Programme is to prevent diabetes whenever possible and, where not possible, to minimize complications and maximize quality of life. The overall goal of the Diabetes Programme is to improve health through stimulating and supporting the adoption of effective measures for the surveillance, prevention and control of diabetes and its complications, particularly in low- and middle-income countries. 5

J INDIAN MED ASSOC, VOL 114, NO 4, APRIL 2016

The above goal is addressed by focusing on the following core functions. These functions are in close alignment with the core functions of WHO: •

•

To oversee the development and adoption of internationally agreed standards and norms for the diagnosis and treatment of diabetes, its complications and risk factors. To promote and contribute to the surveillance of diabetes, its complications and mortality, and its risk factors.

•

To contribute to building capacity for the prevention and control of diabetes.

•

To raise awareness about the importance of diabetes as a global public health problem.

•

To act as an advocate for the prevention and control of diabetes in vulnerable populations. The main goals of the World Health Day 2016 campaign aims to:

•

Increase awareness about the rise in diabetes, and its staggering burden and consequences, in particular in low-and middle-income countries;

•

Trigger a set of specific, effective and affordable actions to tackle diabetes. These will include steps to prevent diabetes and diagnose, treat and care for people with diabetes; and

•

Launch the first Global report on diabetes, which will describe the burden and consequences of diabetes and advocate for stronger health systems to ensure improved surveillance, enhanced prevention, and more effective management of diabetes.

There are two main forms of the diabetes. People with type 1 diabetes typically make none of their own insulin and therefore require insulin injections to survive. People with type 2 diabetes, the form that comprises some 90% of cases, usually produce their own insulin, but not enough or they are unable to use it properly. People with type 2 diabetes are typically overweight and sedentary, two conditions that raise a person’s insulin needs. It may also be seen during pregnancy. The diabetes epidemic is rapidly increasing in many countries, with the documented increase most dramatic in low- and middle-income countries. A large proportion of diabetes cases are preventable. Simple lifestyle measures have been shown to be effective in preventing or delaying the onset of type 2 diabetes. Maintaining normal body weight, engaging in regular physical activity, and eating a healthy diet can reduce the risk of diabetes. Diabetes is treatable. Diabetes can be controlled and managed to prevent complications. Increasing access to diagnosis, self-management education and affordable treatment are vital components of the response. Efforts to prevent and treat diabetes will be important to achieve the global Sustainable Development Goal 3 target of reducing premature mortality from noncommunicable diseases (NCDs) by one-third by 2030. Many sectors of society have a role to play, including governments, employers, educators, manufacturers, civil society, private sector, the media and individuals themselves.

We request you to send Quality Article addressed to : Hony. Editor, Journal of IMA, 53 Sir Nilratan Sarkar Sarani (Creek Row), Kolkata 700 014 Dr. Debasish Mukherjee Hony. Editor

Dr. Santanu Sen Hony. Secretary

Originals and Papers Retinopathy of prematurity screening in a rural based hospital of central India Kanav Gupta1, Rekha Khandelwal2, Shashank Bidaye3, Mohana Majumdar4 Purpose of this study is to perform Retinopathy of Prematurity (ROP) screening, to identify infants who have or are likely to develop ROP and to suggest recommendations based on it. This hospital based prospective study was carried out in 50 preterm babies over 18 months period. Indirect ophthalmoscopy was performed in infants with gestational age < 36 weeks and/or birthweight < 2000 gm. Maternal and neonatal risk factors were noted and data analyzed statistically. The patients were divided into two groups A and B, Group A comprising of babies with stage 1 and 2 ROP and Group B comprising of Stage 3-5 ROP. Twenty two percent babies developed ROP. One third positive cases were weighing < 1500 gm. 39% were < 30 weeks gestation .Sepsis and Intra Ventricular Haemorrhage (IVH) were independent and statistically significant risk factors (p<0.05). Antenatal steroid administration (p = 0.001), reduced the occurrence of ROP. We recommend ROP screening at 4 - 6 weeks of post natal age in all preterm babies with birthweight < 2000 gm and/or gestational age < 36 weeks. Judicious use of oxygen has a significant effect on reduced incidence of ROP. [J Indian Med Assoc 2016; 114: 7-11]

Key words : Retinopathy of prematurity, preterm babies, oxygen therapy, low birth weight babies.

MATERIALS AND METHODS

etinopathy of Prematurity (ROP), a potentially blinding condition is a proliferative disorder of the developing retinal vasculature seen in the preterm and low birthweight infants, first described by Terry1 as Retrolental Fibroplasia.

A hospital based, prospective observational study was conducted in Department of Ophthalmology in collaboration with Department of Pediatrics, in a rural based hospital of Central India, between 2008-2011. All relevant perinatal data including risk factors (Maternal and Neonatal) were documented.

The outcome ranges from minimal sequel to bilateral, irreversible and total blindness. Incidence of this condition is rising rapidly in developing countries with improvements in neonatal care and increasing survival of very low birthweight infants.

Inclusion Criteria : 1) Gestational age at birth of less than 36 weeks 2) Birthweight less than 2000 gms

The most important determinant of any ROP management program is an effective screening strategy. Three questions: Whom to screen? When to screen? and How to screen? are important questions which we must answer in the Indian Scenario.

3) Extraordinary support of oxygen 4) Complete documentation of hospital records including details regarding other factors that can increase the risk of ROP and where screening should be considered were preterm babies with:

Hence the present study was undertaken to screen the preterm infants for ROP which if untreated may cause severe visual disability.

a. Respiratory Distress Syndrome b. Sepsis c. Sickly Survivors d. Pneumonitis

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

2,3

e. Multiple Blood Transfusions

Department of Ophthalmology, NKP Salve Institute of Medical Sciences & Lata Mangeshkar Hospital, Nagpur 440019 1 MS, Fellow Vitreo Retina 2 MS, FICOProfessor & Head 3 DO, DNB, FRFLecturer 4 DOMSAssistant Lecturer

f. Multiple births (twins/triplets,etc.) g. Apnoeic episodes h. Intraventricular hemorrhages 7

RETINOPATHY OF PREMATURITY SCREENING IN A RURAL BASED HOSPITAL OF CENTRAL INDIA — GUPTA ET AL

J INDIAN MED ASSOC, VOL 114, NO 4, APRIL 2016

Exclusion Criteria: 1) Babies with congenital anomalies of the eye 2) Babies with chorioretinitis 3) Babies with birth trauma 4) Babies lost to follow up First examination was carried out in NICU between 4-6 weeks postnatally under all aseptic precautions and following standard ROP screening guidelines. Subsequent examinations were done at 2-3 weeks interval or even earlier, if necessary till retina was fully vascularised. Classification of ROP was done according to the International Classification (ICROP).

picture, changes in the leucocytes count, elevated Creactive proteins and positive culture report. Follow up screening and management of ROP was done as per guidelines given by American Academy of Pediatrics.

in WHO's VISION 2020 it is given high priority. Early treatment to prevent blindness due to ROP requires qualified and trained ophthalmologist, who can do ROP screening in babies at risk in NICU soon after birth.

A prospective statistical analysis was done on the data using the Excel and R programming software package.

The incidence of prematurity has increased over the few years. With increasing incidence of prematurity and better survival of smaller babies, the incidence of ROP was expected to increase. Hence an attempt was made in the current study to look at the incidence of ROP in a rural based hospital.

RESULTS

During the study period of 18 months, the total no of babies <36 weeks gestation and <2000 gms at birth was 138. However 50 babies fulfilled all the inclusion criteria and were included in the study, rest were lost to follow up/died and were excluded from the study.

4,5

Babies with stage 1 - 2 disease were kept in ROP Group A and those with (more severe disease) stage 3 - 5, were kept in ROP Group B. Neonatal and maternal risk factors were documented. Babies were examined by dilating the pupils with diluted Tropicacyl Plus (0.5% Tropicamide+ 2.5% Phenylephrine) eye drops in 1:2 dilution using distilled water. Eyes were examined 30 minutes after application of the first drop. Excess drops spilling over were wiped with sterile cotton to prevent systemic complications. Eyes were examined by indirect ophthalmoscopy with a condensing lens of +20D. An infantile eye speculum was used to keep the eyes open. Oculocephalic reflex and scleral depression were used to examine peripheral retina. Babies with ROP were scheduled for screening as follows: the examinations were performed weekly for stage 1-2 disease and more frequently for stage 3 disease, till the disease started resolving or progressed to threshold stage. Babies showing evidence of regression were followed up weekly till vascularisation was complete. Babies progressing to threshold stage were treated with laser. Screening was continued till term gestation and subsequent follow up was done in 3 to 6 months. 6

Neonatal risk factors like sex, birthweight (in grams), gestational age (in weeks), details of oxygen saturation, blood transfusion, sepsis, apnoea, intraventricular hemorrhage, Indomethacin used for Patent Ductus Arteriosus, Aminophylline, acidosis (PH<7.3), phototherapy, necrotizing enterocolitis, seizures were recorded for risk factor analysis. Maternal risk factors like type of delivery, twin pregnancy, premature rupture of membranes, maternal diabetes, pregnancy induced hypertension, antenatal steroids, oligohydramnios and whether the baby was inborn or outborn, were recorded. All infants receiving Oxygen therapy had continuous monitoring with Pulse Oximetry and Arterial Blood Gas Analysis through umbilical or peripheral arterial blood sampling. Apnoea was defined as cessation of respiration for > 20 seconds which required resuscitation with Bag Mask and Oxygen. Sepsis was diagnosed by clinical

Problems encountered during screening were minimal and related to scleral indentation. None developed conjunctivitis, apnoea, cyanosis or hypothermia during examination. No problems were encountered due to mydriatic use. Eleven of the 50 preterm babies (22%) developed ROP and all had bilateral disease. There were 10 males and 1 female infant with ROP. Eight babies were in Group A (Stage 1 - 2) and 3 were in Group B (Stage 3 - 5). The birthweight of ROP babies ranged from 968-1650 grams with mean weight of 1260.90 ± 215.52 grams while that of non-ROP babies ranged from 900-2900 grams with mean weight of 1517.07 ± 419.04 grams. On similar lines, mean weight of babies in group A was 1309.75 ± 226.19 grams and group B was 1130.66 ±134.84 grams. The gestational age of ROP babies ranged from 28-36 weeks with mean gestational age of 30.54 ± 2.54 weeks while that of non-ROP babies ranged from 28-39 weeks with mean age of 33.12 ± 3.05 weeks. Also the group wise tendencies were obtained. The mean gestational age of babies in Group A was 30.75 ± 2.81 weeks and Group B was 30 ± 2.81respectively.

In the present study, 50 babies admitted to NICU and satisfying the inclusion criteria during the study period were screened for ROP. Flynn and others have highlighted the fact that if retinal examination is too soon after birth, acute retinopathy of prematurity is missed as changes often develop later in more preterm infants. Equally if the examination is too late any acute changes may have regressed and no sequeale can be detected. According to American Academy of Ophthalmology guidelines, the first examination should normally be performed between 4 and 6 weeks of chronologic (postnatal) age or, alternatively, within the 31st to 33rd week of postconceptional or postmenstrual age (gestational age at birth plus chronological age), whichever is later, as determined by the infant’s attending pediatrician or neonatologist. 7

The incidence of ROP in the present study is 22.00% which is well within the range reported from other studies as shown in Table 4. An Indian study by Gupta et. al. in 2004 reported incidence of 21.7%. 8

Lower birthweight (<1250 grams) was associated with stage III and above ROP. Maximum number of ROP cases were seen in birthweight between 1000-1500 grams.ROP stage I and II (Group A) was found in eight babies(72.72%) where as advanced ROP stage III and above (Group B) was found in three babies (27.27%).

The Scatter Plot as shown in Figure 1 revealed that, for a cut-off weight of 1500 gm, the incidence of ROP was statistically significant (p=0.045). Nearly, 31% of the babies weighing less than 1500 gm were affected. Further, a cut-off gestational age of 30 weeks indicated significant number of incidences (p=0.040). Nearly 39% of the babies were affected with age less than or equal to 30 weeks.

Rekha et al reported ROP in 46% infants weighing less than 1500 grams and less than 34 weeks. We reported seven ROP positive cases (63.63%) between 28-30 weeks of gestation which forms the majority group of ROP. Hence, lower gestational age was significantly associated with increased incidence of ROP.

The statistical significance of difference between the ROP +ve and ROP –ve cases was compared and analyzed using independent t-test. The results are shown in Table 1.Various neonatal risk factors were studied and their significance is shown in Table 2.The impact of some of the key factors of interest was studied on ROP and shown in Table 3. The factors identified were either singleton or in combination with the ‘inborn’ or ‘out born’ category.

Various studies as shown in the table 4 have taken variable inclusion criteria. In some studies less gestational age and/or weight is taken and in others they have taken either gestational age or only weight as inclusion criteria. In order to include all ROP positive cases we have included all babies with gestational age less than 36 weeks and /or birthweight less than 2000 gms as suggested by Jalali et al.

DISCUSSION

ROP is an avoidable cause of childhood blindness and

In our setup we have found ROP positive cases both above and below the gestational age of 32 weeks and birthweight of 1500 grams .As the inclusion criteria were

Table 1 — Comparison of Birth Weight and Gestational age of Infants with and without Rop Characteristics

ROP +ve

ROP –ve

t-value p-value

Birth weight 1260.90±215.52 1517.07±419.04 -2.7424 0.0097 Gestational age 30.54±2.54 33.12±3.05 -2.8392 0.0105

Table 2 — Neonatal Risk Factors for Prematurity Neonatal Risk Total babies Factors

Babies with p- value SigniROP (one-sided) ficance

Oxygen Exposure36(72.00%) RDS 14(28.00%) Blood transfusion21(42.00%) Apnoea 8(16.00%) PDA 1(2.00%) Phototherapy 23(46.00%) Sepsis 23(46.00%) IVH 4 (8%) Fetal Distress 18 (36%) HMD 5 (10%)

8(22.22%) 3(21.42%) 6(28.57%) 3(37.50%) 0 5(21.73%) 8(34.78%) 3(75.005) 5(27.77%) 1(20.00%)

0.635 0.659 0.269 0.236 0.647 0.04 0.029 0.345 0.73

NS NS NS NS NS S S NS NS

S–Significant; NS–Non Significant Table 3 — Statistical significance on impact of Neonatal Risk Factors on ROP using Binomial Exact Test Risk factors / factor combinations (n=50)

Number of No. of cases successes (No ROP)

Steroids Inborn + Steroids Out born + Steroids Inborn + Oxygen Exposure Out born + Oxygen Exposure

21 13 8 17 19

18 12 6 14 14

p-value

Significance

0.0014 0.003 0.239 0.0127 0.063

S S NS S NS

S–Significant; NS–Non Significant

different it’s not possible to compare results fully. Thus the screening criteria should be less rigid than described in reports from long established centres. Therefore, every country and particularly, different regions should make guidelines based on current and local data. Lower gestational age and low birthweight are the most important risk factors for the etiology for ROP in our study and it is well recognized that the incidence and severity of ROP are inversely proportional to gestational age and birthweight. In our study mean gestational age of infants who developed ROP (30.54±2.54 weeks) was lower than those who did not develop ROP (33.12±3.05 weeks) and was statistically significant with p=0.0105. The mean birthweight of babies who developed ROP (1260.90±215.52 grams) was lesser that those who did not develop ROP (1517.07±419.04 grams) and was statistically significant with p=0.0097.

RETINOPATHY OF PREMATURITY SCREENING IN A RURAL BASED HOSPITAL OF CENTRAL INDIA — GUPTA ET AL

J INDIAN MED ASSOC, VOL 114, NO 4, APRIL 2016

Various neonatal risk factors for Table 4 — Incidence from National and International Studies ROP were studied. Out of all preterm babies (n=50) we reported 23 babies Author/Year /place No. Inclusion criteria Incidence of ROP (46.00%) with sepsis and eight babies (34.75%) among them developed Gestational Birth Overall % Severe % ROP which was statistically age weight (weeks) (grams) significant (p=0.04). Six out of these eight preterm babies were outborn i.e. International Studies : they were delivered outside our Schalij Delfos 1996 Amsterdam 581 <32 <1500 27.4 NM hospital and were referred here, which Bullard 1995 USA 92 <1251 41.3 4.3 explains the high incidence of sepsis Chye 1999 Malaysia 100 <37 <1250 15.0 4.0 in these cases. Al-Essa 1999 Kuwait 130 <36 <2000 45.4 NM Hussain 1999 USA 950 <37 21.3 NM Another important risk factor in Fledelius 2000 Denmark 177 <32 <1750 10 NM our study was IVH which was also Blair 2001 USA 191 <1250 38 16 statistically significant (p=0.029). Nair 2003 Oman 59 <32 <1500 25.4 10.2 The present study clearly highlights the importance of antenatal Studies from India : Charan 1995 165 <1700 47.3 4.9 steroids in the prevention of ROP. Gopal 1995 50 <2000 38.0 16.0 Antenatal steroid use has been Rekha 1996 100 <34 <1500 46.0 8.0 recommended for pregnancies of 24 to Maheshwari 1996 66 <35 <1500 20.0 7.0 34 weeks of gestation with threatened Dharwani 1996 55 <2000 47.2 NM premature delivery to decrease the Patil 1997 40 <32 <1250 17.5 0 risk of RDS and neonatal death in Verghese 2001 79 <34 <1500 51.9 6.3 preterm neonates. Gupta 2004 60 <35 <1500 21.7 5.0 Present study 2010 50 <36 <2000 22 27.27 In our study, 21 preterm cases had history of antenatal steroid administration. Out of these, 18 babies did not develop ROP which showed antenatal steroid administration helps in non occurrence of ROP and was statistically significant (p=0.0014). Antenatal steroids administration to reduce the incidence of ROP was also reported by Higgins et al. The causal link between ROP and supplemental oxygen has been confirmed by controlled trials and clinical studies. Preliminary work has suggested that continuous oxygen monitoring may reduce the incidence of ROP. In our NICU, oxygen administration, its flow rate and duration are not based solely on clinical findings like cyanosis, respiratory distress or heart rate, but are closely monitored by pulse oxymetry and oxygen saturation is kept between 88-94%. Although oxygen administration was a Fig 1 — Scatter Plot Showing the Distribution of Cases According significant independent risk factor of to Gestational Age and Birth Weight ROP, but in our study, 14 out of 17 inborn babies (i.e. babies born in our hospital) were given oxygen Group A (ROP Stage I and II) included eight patients of judiciously and so they did not develop ROP which was statistically significant (p=0.0127) as compared to babies ROP and were followed up closely. A significant number delivered and managed outside our hospital (outborn) who of babies (n=8, 72.72%) regress without reaching showed increased incidence of ROP. threshold disease in our study and is comparable to other The management of ROP basically depends on studies in literature as reported by Azad RV et al. The decreased incidence of ROP in the present study findings of ROP screening and follow up screening once ROP is detected .In our series of eleven cases ,three cases could be attributed to the improved neonatal nutritional were in Group B ( ROP stage III and above) and needed support, continuous pulse oxymetry, and judicious use of laser therapy . Oxygen. The reduced incidence could also be due to low 62

survival of extreme preterm babies and limited sample size. Since ROP is essentially asymptomatic in the early stages, standards of practice now demand carefully timed retinal examinations of at risk infants. Guidelines for ROP screening in Indian scenario should be gestational age of less than 36 weeks and birthweight less than 2000 grams to avoid missing ROP cases. Good team work of Obstetrician, Neonatologist and an Ophthalmologist is vital and they should work in close cooperation to detect ROP early and manage it. Parents of at risk babies should be properly counselled so that they understand the severity of blinding complications and the need of lifelong follow up. REFERENCES 1 Terry TL — “Extreme prematurity and fibroblastic overgrowth of persistent vascular sheath behind each crystalline less 1. Preliminary Report. American Journal of Ophthalmology 1942; 25: 203-204. 2 Jalali S, Matalia J, Hussain A, Anand R — Modification of screening criteria for ROP in India and other Middle Income Countries. American Journal of Ophthalmology 2006; 141: 966-8. 3 Jalali S, Anand R, Kumar H, Dogra MR, Azad R, Gopal L — Programme planning and screening strategy in retinopathy of prematurity. Indian Journal of Ophthalmology 2003; 51: 89-99. 4 Committee for the classification of retinopathy of prematurity. An international classification of retinopathy of prematurity. Archives of Ophthalmology 1984; 102 : 1130-4. 5 Committee for the classification of retinopathy of prematurity. An international classification of retinopathy of prematurity, II: the classification of retinal detachment. Archives of Ophthalmology 1987; 105 : 906-12. 6 Maheshwari R, Kumar H, Paul VK, Singh M, Deorari AK, Tiwari AK — Incidence and risk factors of retinopathy of prematurity in a tertiary care newborn unit in New Delhi. National Medical Journal of India 1996; 9: 211-4. 7 Flynn JT, O’Grady, GE, Herrera J — “Retrolental fibroplasias I clinical Observation” . Archives of Ophthalmology 1977; 95: 217-23.

8 Gupta VP, Dhaliwal U, Sharma R, Gupta P, Rohatgi J — Retinopathy of Prematurity-Risk Factors: Indian Journal of Pediatrics 2004;71: 887-92. 9 Rekha, Battu S, RR, Chandrashekhara, MK — “Retinopathy of Prematurity- A Preliminary report”. Indian Journal of Pediatrics 1992; 29: 623-6. 10 Higgins, RD, Mendelsohn, AL, Defeo, JJ — “Antenatal Dexamethasone and decreased Severity of Retinopathy of Prematurity”. Archives of Ophthalmology 1998; 116: 601-6. 11 Charan, R, Dogra, MR, Gupta, A — “The incidence of retinopathy of prematurity in a neonatal care unit”. Indian Journal of Ophthalmology 1995; 43: 123-6. 12 Raj VA — Retinopathy of Prematurity; A Text and Atlas, In: Raj VA; New Delhi. Jaypee Brothers 2006: 41-2.

A RANDOMIZED STUDY COMPARING EFFICACY AND SAFETY OF MILNACIPRAN — DALAI ET AL 13

Originals and Papers A Randomized study comparing efficacy and safety of milnacipran versus escitalopram on patients of major depressive disorder 1

9,10

The objective of the study was to compare the efficacy and safety of milnacipran and escitalopram in the treatment of patients of major depressive disorder (MDD). The study was conducted in 60 patients suffering from major depressive disorder as per Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria. Patients were randomized into two groups and were given either milnacipran (50mg OD) or escitalopram (10mg OD) for 8 weeks. The primary efficacy parameter was the change in Hamilton Depression Rating Scale -17 items (HDRS-17) where as the change in Montgomery –Asberg Depression Rating Scale (MADRS) was the secondary parameter. Safety evaluation was based on the treatment emergent adverse effects and laboratory investigations. There was significant decrease in HDRS-17, MADRS from baseline to endpoint (p<0.001) in both the groups. However the difference in scores between two groups was not statistically significant. The mean HDRS-17 score decreased from26.28 (SEM 0.48) to 9.88 (SEM 0.52) in milnacipran group and from 25.70 (SEM 0.64) to 11.08 (SEM 0.46) in escitalopram group at the end of therapy. There was no significant difference in adverse effects and laboratory parameters between the two groups. So these findings of this study indicate that milnacipran 50mg is equally effective to escitalopram (10mg) in patients of major depressive disorder (MDD). [J Indian Med Assoc 2016; 114: 12-6]

Key words : Milnacipran, Escitalopram, Major Depressive Disorder. MDD continues to be a considerable problem, both for clinician and the public health level. It is currently the fourth leading cause of disease and disability worldwide and is projected to rise to second in 2020.

ajor depressive disorder (MDD) is defined as depressed mood on a daily basis for a minimum duration of 2 weeks. An episode may be characterized by sadness, indifference, apathy, or irritability and is usually associated with: changes in sleep patterns, appetite, and weight; motor agitation or retardation; fatigue; impaired concentration and decision-making; feelings of shame or guilt; and thoughts of death or dying.

Various groups of antidepressant medication available in the market, namely monoamine oxidase inhibitors (MAOs), tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs) and selective serotonin-norepinephrine reuptake inhibitors (SNRIs).

MDD is a common and serious mental illness with sometimes fatal consequences that imposes a significant disease burden on the individual in terms of impaired functioning and health-related quality of life (HR-QOL).

MAOIs are not used regularly due to its side effectslike orthostatic hypotension and weight gain etc. 4

TCAs are not preferred these days because of their adverse effect profile i.e. anticholinergic effects, cardiac arrhythmias and seizure precipitation.

MATERIAL AND METHODS

Ethical Considerations : The study protocol, along with the informed consent form (in Bengali, Hindi& English) was submitted to the Institutional Ethics Committee, R. G. Kar Medical College, Kolkata, for approval. Subject recruitment commenced only after such approval was obtained in writing. Informed written consent was taken from each participant. Illiterate patients gave their left thumb impression instead of signature in the presence of an appropriate witness.

Study Setting : • Screening: Through out-patient department (OPD) R.G.Kar Medical College, Kolkata (R.G.K.M.C). • Recruitment and Drug dispensing: Through Psychiatry OPD of R.G.K.M.C. • Data compilation and Statistical analysis: In Department of Pharmacology, R.G.K.M.C.

Study Duration :

Final Year MD PGT (Pharmacol), Department of Pharmacology, R G Kar Medical College, Kolkata 700004 MD (Pharmacol), Associate Professor, Department of Pharmacology, NRS Medical College, Kolkata 700014 MD (Psychiatry), Associate Professor, Department of Psychiatry, RG Kar Medical College, Kolkata 700004 MD (Pharmacol), Demonstrator, Department of Pharmacology, RG Kar Medical College, Kolkata 700004 MD (Psychiatry), Assistant Professor, Department of Psychiatry, RG Kar Medical College, Kolkata 700004 Second year MD PGT (Anaesthesiology), Department of Anaesthesiology, National Medical College, Kolkata 700014 1

SSRIs are presently the most widely used antidepressants because of their better safety profile and tolerability. SSRIs selectively blocks neuronal transport of serotonin and increase synaptic availability of serotonin. Escitalopram, the S-enantiomer of citalopram, is an (SSRI) antidepressant that is the most selective of the SSRIs. The efficacy and safety of escitalopram has been well established in the treatment of MDD.

5,6

Subject Selection Criteria : Patients attending the psychiatry OPD of R.G.K.M.C. with clinical features of major depressive disorder fulfilling the DSM-IV criteria were recruited in the study if they fulfilled the following inclusion and exclusion criteria.

Chanchal Kumar Dalai , Tapas Jyoti Roy , Gautam Bandyopadhyay , Shirsendu Mondal , Sayanti ghosh5, Sushobhan Pramanik1, Madhumita Ray6

SNRIs inhibit reuptake of neurotransmitters, serotonin and norepinephrine. This results in an increase in the extracellular concentrations of serotonin and norepinephrine in the brain that are known to play an important role in mood. Among the SNRIs milnacipran has the best 5-HT/NA inhibition ratio irrespective of the dosage(5HT:NA-1.6:1) and has ideal pharmacokinetic parameters,alleveation of all symptoms of depression. In a meta-analysis of two studies comparing milnacipran with SSRIs- fluoxetine and paroxetine, milnacipran was found to be significantly more effective than SSRIs. So till now we didn’t know which is the better choice for the treatment of MDD with respect to efficacy and safety, either escitalopram or milnacipran. Medline search at the inception of this study did not show any published data on the efficacy and safety of milnacipran vs escitalopram amongst major depressive population. Hence, the present study was designed to compare short term efficacy and safety of milnacipran and escitalopram in the treatment of major depressive disorder.

For each enrolled subject the total duration of therapy was eight weeks (8 wks).

Inclusion Criteria : • Age: 18-65 years • Sex: Either sex • Major Depressive disorder based on DSM-IV criteria baseline score of=17of 17 item HDRS-17.

Exclusion Criteria : • Patients with clinically significant renal or hepatic disease or any other chronic medical illness • alcohol or drug abuse within the past one year • history of myocardial infarction or unstable heart disease within past 6 months • acute coronary syndrome within past 6 months • known or suspected pregnancy or breast feeding • Use of any antidepressant within past 30 days or participation in any other clinical trial within 3 month

Sample Size : For the purpose of sample size calculation, changes in the Hamilton Depression Rating Scale-17 Items12, 13 (HDRS-17) was taken as the criteria. The study was designed to detect at least a difference of 2 HDRS-17 score between the two treatment groups, considering level of significance 5% ( a of 0.05) and 80% power, we required 48 patients (24 in each group). Assuming a drop out rate to be 20% we included a total of 60 patients. Sample size calculation was done by using Win Pepi ver 11.1 software.

Blinding : Study was designed as assessor-blind study so that assessor was not aware of the group allocation of individual subjects.

Randomization : The estimated sample size for the study (including dropouts) was 60 (30 in each group).A random number table generated by computer was used to allocate patients to treatment groups, and the study coordinator was the only person with access to the randomization.

Study Design :

Treatment Schedule :

The current study was designed as a prospective, interventional, randomized, assessor blind, activecontrolled, fixed dose with two parallel treatment groups was carried out at a single Centre.

Patients were randomized (generated by computer) into two groups and were started on either milnacipran 50mg orally with a glass of drinking water after dinner or escitalopram 10 mg in the same manner. The follow up visits were at the end of 2nd week (FU-1) and after end of

J INDIAN MED ASSOC, VOL 114, NO 4, APRIL 2016

8th week (end of the study-EOS). At each visit efficacy and safety was evaluated and drug was supplied. Compliance was checked by pill countmethod at each follow up visit. The drop outs or withdrawal if any along with reasons for the same were recorded. Data was collected in a specially designed case report form (CRF) by conducting a personal interview with each patient during the clinic visit.

A RANDOMIZED STUDY COMPARING EFFICACY AND SAFETY OF MILNACIPRAN — DALAI ET AL 15

cline in HDRS-17 score in both the study groups over the period of treatment of 8 weeks when any of the follow-up visits was compared with the corresponding baseline (p value <0.001 by Friedman ANOVA test followed by post hoc analysis of Dunn’s Multiple Comparison test).However there was no statistically significant difference of HDRS-17 score between the group M and group E at any point of time analyzed by Unpaired‘t’ test.

ASSESSMENT PARAMETERS

The following parameters were assessed at the visits specified:

Efficacy Parameters : Primary efficacy parameter Change of the score of Hamilton Depression Rating Scale-17 Items12, 13 (HDRS-17) – baseline of the study (BS), first follow up at end of 2nd week (FU-1) and end of the study at end of 8th week (EOS). Secondary efficacy parameters Change of the score of Montgomery –Asberg Depression Rating Scale 14 (MADRS)–BS, FU-1,EOS Safety evaluation was based on spontaneously reported adverse effects at any time (by telephone also) and the laboratory investigations at baseline and at the end of study time i.e. end of 8th week. STATISTICAL ANALYSIS

The statistical analysis was done in accordance with the guidelines of modified intention to treat (MITT) analysis. Descriptive statistics were reported as percentages, mean± S.E.M (standard error mean) for continuous parametric variable, and median for continuous nonparametric variables. Fisher’s exact test was employed to test the association of study characteristics between the two treatment groups for categorical variables. Unpaired‘t’ test was employed to find the significance in different treatment over the study period of 8 weeks (p<0.05). Friedman’s ANOVA test followed by Dunn’s Multiple Comparison test was employed to find the significance in the same treatment group in various time period in the study period of 8 weeks, The computer software graph pad inStat version 3.06.was used for all the statistical analysis. RESULT AND ANALYSIS

A total of 60 patients suffering from MDD as per DSM-IV criteria were enrolled in the study. Finally 49 patients (25 subjects in treated with milnacipran -Group M and 24 subjects were treated by escitalopram -Group E) completed the study as per protocol. The patients in both the groups had comparable demographic profiles as shown in Table 1. HDRS-17 SCORE

As observed from Table 2, there was significant de

MADRS SCORE

As seen from Table 3, both the groups show significant decline in MADRS score over the period of treatment of 8 weeks, when compared with the corresponding baseline. Again, there was no statistically significant difference of MADRS score across the groups at any point of the study analyzed by unpaired‘t’ test. Table 1 — Demographics and Mean Baseline Scores Parameters

Group M

Group E ( n = 25)

p value ( n = 24)

Age (in years) : Range 18-55 25-56 Mean ± SEM 36.04 ± 2.09 35.75 ±1.63 Sex : Male 11 (44%) 12 (50%) Female 14 (56%) 12 (50%) Baseline scores (Mean ± SEM), Median : HDRS-17 : (Mean ± SEM) 26.28 ± 0.48 25.70 ±0.64 Median 26 26 MADRS : (Mean ± SEM) 39.92 ± 0.69 39.83 ±0.56 Median 40 40

>0.05 >0.05 >0.05

>0.05 >0.05

Table 2 — Changes in HDRS-17 SCORE (decreasing score means improvement) Group M ( n = 25)

Baseline : Mean ± SEM 26.28 ± 0.48 Median 26 FU -1 (after 2 weeks) : Mean ± SEM 15.04 ± 0.66*** Median 15 EOS (after 8 weeks) : Mean ± SEM 9.88 ± 0.52*** Median 10

During the 8 weeks treatment period, the recruited subjects experienced and spontaneously reported the following adverse events represented in Table 4. None of the events were severe enough to warrant withdrawal from the study, and all resolved spontaneously. There were no hospitalizations owing to adverse events and no serious adverse events. The adverse events were comparable in both groups. Laboratory investigations of hematological and biochemical parameters did not show any significant change at the end of treatment as compared to baseline in both the groups as shown in Table 5. DISCUSSION

Although there are a number of therapeutic choices available for the treatment of major depression, it is generally acknowledged that the current first line therapies provide less than satisfactory outcome in many instances. This is because nearly two-third of all patient are either partially or completely non responsive, only one-third experience full remission and many have tolerability concerns that limit long term treatment .Thus the development of new agents that can meaningfully expand the expected therapeutic effect and tolerability of antidepressant therapy option is an important medical need. 4

>0.05 >0.05

p value for comparison between the study groups for age and baseline score is from Student’s unpaired t test, while for sex distribution is from Fisher’s exact test.

Visits

TREATMENT EMERGENT ADVERSE EVENTS

Group E ( n = 24)

p value

25.70 ±0.64 26

0.48

15.95 ± 0.57** 16

0.30

11.08 ± 0.46*** 12

0.09

*** means p<0.001, **means p<0.01. p value for comparison between the study groups was from Unpaired‘t’ test. While p value for within group comparison of any of the follow up visits to the corresponding baseline is Friedman ANOVA test with Dunn’s Multiple Comparison test as post hoc test.

The present study was a randomized controlled clinical trial to evaluate the efficacy and safety of a new group of antidepressant-milnacipran (SNRI) in comparison to escitalopram (SSRI) in the patients of major depressive disorder. They are assigned to two treatment groups by randomization. The groups were comparable at baseline with respect of age, sex, weight and baseline scores of HDRS-17, MADRS scale. Both treatments were effective in improving the various symptoms of the disease. The primary efficacy variable was the scoring obtained on the HDRS-17 scales. And the secondary efficacy variable was the scoring obtained on the MADRS scales.

Table 3 — Changes in MADRS SCORE (decreasing score means improvement) Visits

Group M ( n = 25)

Baseline : Mean ± SEM 39.92 ± 0.69 Median 40 FU -1 (after 2 weeks) : Mean ± SEM 23.96 ± 0.57*** Median 22 EOS (after8 weeks) : Mean ± SEM 15.6 ± 0.88*** Median 16

Group E ( n = 24)

p value

39.83 ±0.56 40

0.92

25 ± 0.75** 26

0.12

16.5 ± 0.87*** 16

0.47

Group M

Nausea Vertigo Sweating Insomnia Dry mouth Headache Constipation Diarrhea

16 8 10 4 10 5 5 2

Group E 12 4 8 10 6 7 3 4

MADRS scale from baseline to study end were significantly less for both milnacipran (mean ± SEM,baseline-39.92 ± 0.69,study end-15.6 ± 0.88,p value-,0.001 ) and escitalopram(mean ± SEM,baseline39.83 ±0.56,study end- 16.5 ± 0.87,p value-0.001 ) drugs. But there were no significant difference between the two MADRS score at study end between the two treatment groups. Regarding safety and tolerability in our study, both treatments were well accepted as assessed by clinical and laboratory parameters.

The changes of score of HDRS-17 from baseline to after 8 weeks were significantly less for both milnacipran (mean ± SEM,baseline-26.28 ± 0.48, study end-9.88 ± Table 5 — Laboratory test profile in the study groups (Values are Mean ±SEM) 0.52 ,p value-0.001 ) and escitalopram(mean ± SEM, Parameters Group M Group E baseline-25.70 ±0.64,study end- 11.08 ± 0.46,p valueBaseline End of study Baseline End of study ,0.001 ). But there were no Hemoglobin(gm/dl) 14.08 ± 0.1625 14.28 ± 0.1583 14.12 ±0.1735 14.33 ± 0.15 significant difference in Total leukocyte count(/dl) 6603.92 ±211.53 6492.8 ± 179.42 6793.75 ± 268.52 6585 ± 202.05 HDRS-17 score at the end of Total bilirubin(mg/dl) 0.778 ± 0.0191 0.744 ± 0.0233 0.763± 0.0359 0.756± 0.0326 the study between the two ALT(IU/L) 32.8 ± 0.9416 33.8 ± 0.9074 31.70 ± 1.088 33.75± 1.034 Creatinine (mg/dl) 0.74 ± 0.0173 0.772 ± 0.0168 0.75 ± 0.0199 0.73 ± 0.0155 treatment groups. Fasting blood sugar(mg/dl)

The changes of score of ALT=Alanine aminotransferase

80.16± 0.8158

81.64 ± 0.9948

81.45± 1.199

79.91± 1.003

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J INDIAN MED ASSOC, VOL 114, NO 4, APRIL 2016

The result of the study corroborates with the previous clinical trials like trials on escitalopram vs duloxetine or escitalopram vs venlafexine .No significant difference of efficacy and safety of escitalopram vs duloxetine or venlafexine (SNRIs) was observed in both the above mentioned trials. The results of this study contradict with the previous trials based on comparison of milnacipran with other SSRIs in depression. In a study it was seen that the efficacy of milnacipran was significantly better than fluoxetine (SSRI) although side effects were not significantly differ. Another study it was seen that milnacipran was superior in efficacy to SSRIs (fluoxetine, fluvoxamine) and equally tolerated. Adverse drug reactions were encountered in both the treatment groups, mainly in the first week but most of them were well tolerated after two to three weeks. The most common events were nausea (16 out of 25 patients in group M, 12 out of 24 in group E).No statistically significant difference was found between the two groups in terms of adverse events. None of the treatment emergent adverse events was severe enough to warrant withdrawal from the study. The present study had some limitations like the treatment period was relatively short (8weeks). Due to time constraint escalation to higher doses was not possible. Though we all know that depression is sometimes self-limiting, in the present study, it was not possible to add a placebo group. In conclusion, the findings of this study indicates that milnacipran,at the dose of 50 mg/dayis an effective and safe antidepressant in comparison to escitalopram at the dose of 10 mg/day in the patient of MDD. 15

REFERENCES 1 Victor, Reus: part 16 neurologic disorders: 386 mental disorder Kasper, Braunwald, Fauci, Harrison’s Principles of Internal Medicine 17 th edition: McGraw-Hill Medical Publishing: 2008: 2716. 2 Xie F, Despiegel N, Danchenko N ,Hansen K — Cost effectiveness analysis of escitalopram compared to venlafaxine and fluvoxamine in treatment of major depressive disorder. International Journal of Psychiatry in Clinical Practice 2009; 13: 59-69. 3 Grover S, Dutt A , Avasthi A — An overview of Indian research in depression . Indian journal of psychiatry 2010; 52: 178-88. 4 Dinesh K Badyal, Prem P Khosla, Rajinder S Deswal,Prithpal S Matreja — Safety and Efficacy of Duloxetine Versus Venlafaxine in Major Depression in Indian Patients JK Science : Journal of Medical Education & Research: 2006: 8:95-199. 5 Burke WJ, Gergel I, Bose A — Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients. J Clin Psychiatry 2002; 63: 331-6.

6 Wade A, Lemming OM, Hedegaard KB — Escitalopram 10mg/day is effective and well tolerated in a placebocontrolledstudy in depression in primary care. Int Clin Psychopharmacol 2002;17: 95-102. 7 Stahl SM — SNRIs: Their Pharmacology, Clinical Efficacy, and Tolerability in Comparison with Other Classes of Antidepressants. CNS Spectrum 2005; 10:732-47. 8 Puozzo C — Pharmacology and pharmacokinetics of milnacipran. Int. Clin. Psychopharmacol 2002; 17: S25-S35. 9 Guelfi JD — A double-blind comparison of the efficacy and safety of milnacipran and fluoxetine in depressed inpatients. Int. Clin. Psychopharmacol 1998; 13:121-8. 10 Sechter D — A comparative study of milnacipran and paroxetine in outpatients with major depression. J Affect Disord 2004; 83: 233-6. 11 Diagnostic and Statistical Manual of Mental Disorder, 4th ed. text revision (DSM-IV-TR). Washington DC: AmericanPsychiatric Association, 2000: 356. 12 Hamilton M — Rating scale for depression. J Neurosur Psychiatry 1960; 23: 56–62. 13 Hamilton M — Development of a rating scale for primary depressive illness. Br J SocClinPsychol 1967; 6:278–296. 14 Montgomery SA, Åsberg M — A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134: 382–9. 15 Khan A, Bose A, Alexopoulos G S, Gommoll C, Li D, Gandhi C — Double-Blind Comparison of Escitalopram and Duloxetine in the Acute Treatment of Major Depressive Disorder. Clin Drug Investig 2007; 27: 481-92. 16 Bielski R J,Ventura D ,Chang C — A Double-Blind Comparison of Escitalopram with Venlafaxine XR in the Treatment of Major Depressive Disorder. J Clin Psychiatry 2004; 65: 1190-6. 17 Lopez IJ, Guelfi JD, Pletan Y, Tournoux A, Prost JF — Milnacipran and selective serotonin reuptake inhibitors in major depression. Int Clin Psychopharmacol 1996; 11: 41-6.

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TO STUDY THE EFFECTS OF HYPERBARIC OXYGEN THERAPY IN CHRONIC DIABETIC FOOT LESIONS — EKBOTE ET AL

Practitioners' Series

and level of amputation if necessary.

To study the effects of hyperbaric oxygen therapy in chronic diabetic foot lesions G R Ekbote1, Sharad K Waje2, Pankaj Bhalerao2

Table 1 — Clinical data of patients with diabetic foot

Patients were also investigated with complete hemogram, liver and renal profile, X ray chest, ECG and serial blood sugars. Urine sugar chart was maintained as a guide to daily diabetic control.

Parameter Age (yr) (range) Sex (M : F) Duration (yr.) Type of Diabetes : T DM T DM Neuropathy Distal pulses normal Absent

Study group

Control group

56.2 (45-70) 3:1 9.8

59.8 (48-70) 2:1 10.9

The two groups were matched for age and sex as shown in (Table 1). The average hospital stay and 15% 20% 85% 80% amputation rates are depicted in (Table 2). The average 17% 21% hospital stay in the study group was less but this was 87% 79% statistically not significant. The need for major 13% 21% amputation in the study group was significantly less. The *Difference in the groups were not significant; IDDM : insulin mode of wound healing is shown in (Table 3). The dependent diabetes mellitus; NIDDM : non-insulin dependent number of patients requiring skin grafts was higher in the diabetes mellitus study group as there was better local control of infection with HBO and lesser amputations. The results Table 2 — Hospital stay, types of amputations and their indications in patients with of pre and post procedural wound cultures are diabetic foot charted in Table-4. In the study group, there Study group Control group Significance was a significant overall control of wound infections, especially of Pseudomonas and Hospital stay (days) Average 40.6 47 E.coli. Though there was reduction in the Range 23-65 20-68 P = NS staphylococcal and anaerobic infections, it Amputations Major n=2 n=7 p < 0.05 (AK:1, BK :1) (AK : 2, AK : 50) was comparable with the control group. There Minor n=4 n=2 p = NS were no complications related to the HBOT. Indications for major Spreading n=1 n=5 1

To Study the effects of hyperbaric oxygen therapy in chronic diabetic foot lesions, a prospective controlled study was undertaken. Thirty diabetics with chronic foot lesions were randomized to study group (conventional management and 40 sessions of hyperbaric oxygen therapy) and control group (conventional management). The patients were assessed for average hospital stay, control of infection and wound healing. The control of infection spread was quicker. Positive cultures decreased from initial 19 to 3 in study group as against from 16 to 12 in the control group. (p < 0.05). This difference was most pronounced for Escherichia coli. Also, the need for major amputation wa significantly less in the study group (n= 20 as against the control group (n=7) (p< 0.05). The average hospital stay was not affected. We conclude that hyperbaric oxygen therapy can be safely used and is beneficial as an adjuvant therapy in chronic diabetic foot lesions. [J Indian Med Assoc 2016; 114: 18-20]

Key words : Chronic diabetic foot lesions, amputations, Hyperbaric Oxygen (HBO) Hyperbaric oxygen therapy (HBOT), wound healing, complication of diabetic foot, infections in diabetic foot.

an amputation done, above the ankle joint. All others were considered as minor amputations. Antibiotics were administered along with metronidazole. Antibiotics commonly used were cephalosporins and aminoglycosides and were changed according to sensitivity patterns. Diabetic control was achieved with insulin given subcutaneously. Two patients with diabetic ketoacidosis were initially treated with intravenous regular insulin.

iabetes mellitus is the most common of the serious metabolic disorders characterized by long-term complications involving eyes, kidneys, nerves and blood vessels . Diabetic angiopathy leads to chronic foot lesions and has a higher risk of amputation than nondiabetics due to poor control of infection. The emergence of hyperbaric oxygen therapy (HBOT) as an adjunct to therapy of diabetic foot lesions has its basis in the fact that it can reduce anaerobic infection, can improve blood supply and can decrease ischaemic damage to nerves . This prospective study was carried out to evaluate the effect of hyperbaric oxygen in diabetic foot lesions and its use as an adjunctive measure. 1-6

Amputations

DISCUSSION :

Infections Uncontrolled diabetes n = 0 gangrene n=1

n=5

One of the most destructive complications n=1 of diabetes is loss of a limb. Three factors lead AK : above knee, BK below knee, n = No. of patients to tissue necrosis in the diabetic foot viz. neuropathy, infection and ischaemia. Peripheral ischaemia may also result from small vessel Table 3 — Data regarding wound healing in patients with diabetic foot disease. However, it is unlikely that the microvascular disease itself is responsible for foot ulcers . Anaerobic Study group (n) Control group (n) bacteria coexist with aerobic bacteria in most of the cases . Increased partial pressure of oxygen in tissues with HBOT Skin graft 6 2 Stump healing 5 6 bypasses the specific oxygen making haemoglobin Persistent infection 1 3 superfluous . Whether HBOT is useful is diabetic foot lesions where the microvascular disease compromises the n = No. of patients delivery system is not known. 1

The patients were randomly allotted to one of the two groups. One received a complete course of HBOT as an adjunct to the above mentioned treatment (the study group) and the other group (control) received only conventional therapy. The HBOT was given in a monoplace hyperbaric oxygen chamber at Sassoon General Hospital, Pune over a period of 8 weeks. The HBOT was administered at 3 atmospheres pressure for a period of 45 minutes at each sitting. The patient is slid completely into the chamber and the chamber is connected to the patient monitoring panel. Oxygen flow is started (flushing phase) for 2-3 minutes till high oxygen concentration is achieved. The chamber pressure is gradually raised to 3 atmospheric pressures after selecting closed circuit mode. After the therapy, the chamber pressure is gradually reduced to normal.

MATERIAL AND METHOD :

Thirty diabetics with chronic foot lesions were studied over a period of 2 years at our hospital. All patients were admitted. All patients received regular surgical treatment consisting incision and drainage of abscesses and debridement of wound. Locally, the wounds were dressed with eusol (1.25% w/v boric acid and 1.25% w/v of bleaching powder) and / or povidone iodine. In those patients in whom the gangrene / infection ascended above the ankle, amputation was performed to limit the spread of infection and resulting toxemia. Major amputation was defined as

To study the effects of HBOT the following parameters were evaluated : (1) wound cultures-before and after each sitting (2) assessment of local wound daily. In case of amputations, skin flaps were assessed. The other parameters studied were hospital stay, need for amputation

BJ Medical College, Pune 411001 MS, MNAMS, Professor of Surgery, Head of Unit General Surgery, MBBS, Chief Resident, Surgery Unit III 1

In the present study, a reduction in hospital stay was found in patients receiving HBOT. Though not statistically significant, it shows that aggressive medical and surgical management remains essential if the effects of HBO are to be realized . Consequently, this group had a higher rate of skin graftings, minor amputations and repeated debridements in the salvaged limb. The major effect of HBO was seen as the significantly reduced rate of major amputations in the study group. This is because HBO may have successfully achieved local control and prevented spread of the infection proximally. Patients were therefore able to maintain a bipedal gait, with a greatly reduced morbidity. The effect on bacteriology were rather surprising. Overall, HBO controlled the wound infection.

Specifically Pseudomonas and Ecoli were eliminated better than in the controls with conventional therapy. The beneficial effects of HBO may be explained on the following grounds. HBO improves microvascular supply by increasing the amount of oxygen so that gaseous diffusion can occur in relatively avascular or ischaemic areas . Normal fibrobiast proliferation and collagen production requires a local oxygen tension level of 20-40 mm of Hg. Raising this threshold level to 40-50 mm of Hg stimulates greater degree of neovascularisation which may favour definitive local healing. Oxygen is bactericidal to certain anaerobic or microaerophilic organisms because they lack the appropriate enzymes (superoxide dismutase and catalase) necessary to protect them in highly oxygenated environments. 9

April 2016 JIMA Advertiser

J INDIAN MED ASSOC, VOL 114, NO 4, APRIL 2016 REFERENCES : 1 Logerfo FW, Coffrnan JD — Vascular and microvascular disease of the foot in diabetes (implications for foot care). N Eng J Med 1984; 311:1615-9. 2 Debridge L, Appleberg m, Reeve TS — Factors associated with development of foot lesions in the diabetics. Surgery 1980; 93:78-82. 3 Editorial. Pathogenesis of diabetic microangiopathy. Br Med J 1977; 1:1555. 4 McMillan DE — Plasma protein changes, blood viscosity and diabetic microangiopathy. Diabetes 1976; 25:858-64. 5 Barnes AJ, Dormandy TL, Dormandy JA, Slack J — Is hyperviscoity a treatable component of diabetic

microcirculatory disease. Lancet 1977; ii: 789-91. 6 Peterson CM, Jones RL, Koenig BS, Melvin ET, Lehrman MD— Reversible hematological sequelae of diabetes. Ann Int Med 1977; 86: 425-9. 7 Olodart RM, Seitz CR — Effrect of hyperbaric oxygen on Gram negative bacilli. Clin Res 1964; 12:37. 8 Louie TJ, Barlett JG, Tally FP, Gorbach SL — Aerobic and anaerobic bacteria in diabetic foot ulcers. Ann Int med 1976; 85:461-63. 9 Camporesi EM, Moon RE, Grande CM — Hyperbaric medicine: an integral part of trauma care. Crit Care Clin 1990; 6: 203-17.

Preliminary Report

MALARIA INFECTION AND ABO BLOOD GROUPS — SHERLY AND VYAS

Malaria infection and ABO blood groups : a study conducted in the central Indian state of Madhya Pradesh Sherly T D1, G Vyas2

This study was undertaken to find the possible correlation between the frequency of malaria infection and ABO blood groups. Three hundred and fifty one malaria infected subjects were studied. Blood group A has been found to be most vulnerable to malaria infection. This finding corroborates with other studies which showed the relative disadvantage of blood type A when it came to malaria. [J Indian Med Assoc 2016; 114: 22-3]

Key words : Malaria, ABO blood group correlation.

sidered as complicated malaria, with severe anaemia (Hb <5 g/dl), jaundice (serum bilirubin >3 mg/dl) and hypoglycaemia (blood glucose < 40 mg/dl). Of these 14 cases, blood group A accounted for 7 cases (50%). Blood groups B and O claimed 3 (21.43%) and 4 cases (28.57%) respectively. Among 337 cases of uncomplicated malaria, there were 33 incidents of mild (Hb <10 g/dl) to moderate (Hb<8 g/dl) anaemia. Blood group A constituted 20 such cases (60.61%), leaving only 8 to group B (24.24%), 4 to group O (12.12%) , and 1 to group AB (3.03%). DISCUSSION

The available statistics suggest that the most common blood groups in India are O (37%) and B (33%), with O having predominance in the south (38%) and B in the north (37%) . In prevalence, O and B are followed by A (22%). The least common blood group is AB (7%). Going by these statistics, the overall distribution of A, B, O and AB blood groups in Ujjain (the place of this research) would more or less be, 22%, 37%, 34%, and 7% respectively. In this study, however, the people with type A blood are the largest group affected by malaria infection (41.03%). In other words, while blood group A made up only 22% of the general population, it accounted for more than 41% of the study subjects. Blood group A topped in both P falciparum and P vivax infections. Group A accounted for 40.67% of P vivax infections. If mixed infections were included as well, the rate of P falciparum infection for blood type A rose to 45.83%. It was also found that the likelihood of mixed infection is high for blood group A. All these show that blood group A is more susceptible to malaria infection than other blood groups. This finding agrees with some earlier studies which have found blood type A to be more predisposed than other groups to malarial infection . Maybe, antigen A works as a coreceptor for malarial infection. With regard to blood group O, this study’s findings are at variance with earlier studies. It has been suggested by several studies that blood group O is fairly resistant to severe malaria, due to reduced RBC rosetting . This relative advantage which blood group O enjoys is the most significant finding so far in the study of malaria and blood group correlation. In the present study, however, this advantage of blood type O could not be confirmed. It was found that blood group O, like blood group A, has higher frequency of complicated malaria. But it should be noted 10,11

OBSERVATIONS

here has been increasing evidence that ABO blood- group antigens play some significant role in the aetiology and prognosis of malaria . As malaria continues to be a big threat to public health safety, any knowledge of possible correlation between malaria infection and blood groups can be of great use in the diagnosis and treatment of malaria.

Regarding malaria infection and ABO blood types in general, the present research found that (1) blood group A was more susceptible to malaria infection than other blood groups and (2) that the rate of susceptibility to malaria infection for people of blood groups B, O and AB was more or less equal. Out of the total 351 subjects, 144 belonged to blood group A (41.03%). Group A was followed by group B and group O, accounting for 103 (29.35%) and 87 subjects (24.78%)respectively. Seventeen subjects had AB blood type, making only 4.84% of the total number.

1-9

The aim of this research was to examine the rate (frequency) of malaria infection among ABO blood groups. An effort has been made to find out the likelihood of different ABO blood types for infection by different plasmodium types.

On the frequency of plasmodium types in the study population, it was noticed that blood group A ranked high in both P falciparum and P vivax infections, although blood group B rated slightly higher for P falciparum, if mixed infections were excluded. Among 19 unmixed P falciparum subjects, 7 belonged to group A (36.84%) and 9 to group B (47.37%). Group O claimed 2 subjects (10.53%) and group AB, 1 (5.26%).

MATERIAL AND METHOD

The study included 351 malarial parasite positive patients who were treated for malarial infection at Ujjain Charitable Trust Hospital, Ujjain, and RD Gardi Medical College Hospital, Ujjain, from August 2008 to January 2010. The study population was a cross-section of the general population in and around the city of Ujjain, Madhya Pradesh, a low transmission malaria endemic region.

The vast majority of the study subjects were infected with P vivax (93.16%). This is to say, 327 subjects out of 351 had P vivax infection. Of these 327 vivax subjects, 133 were of group A (40.67%), 93 of group B (28.44%), 85 of group O (26%), and 16 of group AB (4.89%).

The data was collected by using a proforma. The collected data was analysed using correspondence analysis. The observed relations between different malarial infections and ABO blood groups were tabulated and the statistical significance of each table was assessed and interpreted.

It was also noticed that blood group A topped in the likelihood of mixed infection as well. Of 5 mixed infection cases, 4 were group A (80%) and 1 was group B (20%). Coming to complications associated with malaria, the present research showed that blood group A had higher frequency of complicated malaria. Out of the total 351cases, there were 14 cases (3.99%) that may be con

Department of Medicine, Ujjain Charitable Trust Hospital and Research Centre, Ujjain 456006 MBBS, DNB Final Year Resident MD, FICP, FICA, FRIPHH, Professor of Medicine, RD Gardi Medical College, Ujjain 456006 1

4-6,12

1-6,8,12

that there were only 14 cases of complicated malaria among 351 subjects under study. No reliable inference can be drawn from the observation of such a small number of samples. ACKNOWLEDGMENT

Sherly TD would like to thank Dr G Vyas, Dr JP Bhagwat, Dr VK Sharma, and Dr BL Bamboria for their help with this research. REFERENCES 1 Carlson J, Wahlgren M — Plasmodium falciparum erythrocyte rosetting is mediated by promiscuous lectin like interactions. J Exp Med 1992; 176: 1311-7. 2 Udomsangpetch R, Todd J, Carlson J, Greenwood BM — The effects of hemoglobin genotype and ABO blood group on the formation of rosettes by Plasmodium falciparum infected red blood cells. Am J Trop Med Hyg 1993; 48: 14953. 3 Rowe A, Obeiro J, Newbold CI, Marsh K — Plasmodium falciparum rosetting is associated with malaria severity in Kenya. Infect Immun 1995; 63: 2323-6. 4 Fischer PR, Boone P — Short report: severe malaria associated with blood group. Am J Trop Med Hyg 1998; 58: 122-3. 5 Barragan A, Kremsner PG, Wahlgren M, Carlson J — Blood group A antigen is a coreceptor in Plasmodium falciparum rosetting. Infect Immun 2000; 68: 2971-5. 6 Rowe JA, Handel IG, Thera MA, Deans AM, Lyke KE, Koné A, et al — Blood group O protects against severe Plasmodium falciparum malaria through the mechanism of reduced rosetting. Proc Natl Acad Sci 2007; 104: 17471-6. 7 Uneke CJ — Plasmodium falciparum malaria and ABO blood group: is there any relationship? Parasitol Res 2007; 100: 759-65. 8 Rowe JA, Opi DH, Williams TN — Blood groups and malaria: fresh insights into pathogenesis and identification of targets for intervention. Curr Opin Hematol 2009; 16: 480. 9 Deepa M, Alwar VA, Rameshkumar K, Ross C — ABO blood groups and malaria related clinical outcome. J Vector Dis 2011; 48: 7-11. 10 Nanu A, Thapliyal RM — Blood group gene frequency in a selected north Indian population. Indian J Med Res 1997; 106: 242-6. 11 Kumar H, Mishra DK, Sarkar RS, Jaiprakash M — Difficulties in immunohaematology: the weak D antigen. Med J Armed Forcees India 2005; 6: 348-50. 12 Cserti CM, Dzik WH — The ABO blood group system and Plasmodium falciparum malaria. Blood 2007; 110: 2250-8.

CURRENT AND FUTURE TRENDS IN THE MANAGEMENT OF THYROID — AGRAWAL AND MEHTA 25

Current Topic

sparing of the tendons and an increase in fibro-adipose tissue (Fig 2). In patients with optic neuropathy there may be compression of the optic nerve by the enlarged extraocular muscles especially at the apex(apical crowding) .

Current and future trends in the management of thyroid associated ophthalmopathy

Treatment :

Thyroid dysfunction should be corrected in all patients.Thyroid dysfunction may be treated with antithyroid drugs or with radio-iodine Activity and Staging : therapy. In randomised trials, radioThe clinical activity score helps in iodine therapy for Graves’ classifying TAO as active or inactive . hyperthyroidism caused progression Components of the clinical activity of ophthalmopathy in about 15% of score are spontaneous retrobulbar patients, whereas antithyroid drugs pain, pain with eye movement, redness did not modify the natural course of of the eyelids, redness of the conjunctiva, swelling of the eyelids, G r a v e s ’ o p h t h a l m o p a t h y. swelling of the caruncle, conjunctival Prophylactic treatment with glucooedema (chemosis). Each component Fig 1 — Showing Bilateral Exophthalmos and corticoid agents may be appropriate is given a score of 1. A total score of 0-2 Marked Retraction of the Upper Eyelid for many patients with Graves’ indicates inactive throid associated ophthalmopathy whose hyperophthalmopathy while a score from 3thyroidism has been treated with 7 indicates active Graves' ophthalradio-iodine therapy especially those mopathy . with high risk factors. Risk factors for Patients with active disease will progression of Graves’ ophthalshow a good response to immunomopathy after radio-iodine therapy suppressive therapy while those with inactive disease will not. include cigarette smoking, severe In addition TAO has been hyperthyroidism (serum triclassified as mild, moderate or severe iodothyronine concentration,>5 nmol (Table 1) . Dysthyroid optic per liter), high levels of thyrotropin2 — CECT Scan (Axial Section) Showing neuropathy and keratopathy both Fig Exophthalmos and Enlarged Medial Rectus receptor antibodies, and uncontrolled indicate that the ophthamopathy is and Inferior Rectus Muscles hypothyroidism after radio-iodine sight threatening and should be treated therapy. immediately. Any risk factor for the progression of ophthalmopathy Another method of classification developed in Vancouver is the VISA classification . This is a clinical if present should be controlled. Smoking (if present) recording form which separates the clinical features of should be stopped.Any concurrent infections should be thyroid ophthalmopathy into the following four treated.The treatment of ophthalmopathy includes p a r a m e t e r s : V ( v i s i o n , o p t i c n e u r o p a t h y ) ; I supportive treatment, glucocorticoids, other (inflammation,congestion); S (strabismus,motility immunosuppressive agents, orbital radiotherapy, surgery. restriction); A (appearance, exposure). International Supportive therapy : This includes lubrication with Thyroid Eye Disease Society has modified these recording forms by consensus of its members and adopted them as topical tear supplements and non-steroidal antiinflammatory drugs, dark glasses and taping of the eyelids their standardised office record . at night to reduce the symptoms of dry eye. Prism glasses are used for the correction of diplopia.Mild Table 1 — Showing Features of Mild and Moderate to Severe Graves’ Ophthalmopathy ophthalmopathy may be treated with local measures alone Characteristic Mild Graves’ Moderate to severe with follow-up every 3 to 6 months as there is a 25% ophthalmopathy Graves' ophthalmopathy chance of it progressing to moderate to severe grade . Eyelid retraction (mm) <2 >2 Glucocorticoids : Vision threatening optic Exophthalmos (mm) <3 >3 Soft tissue involvement Mild Moderate-to-severe neuropathy requires treatment with glucocorticoids.The Extra-ocular muscle None or intermittent Inconstant or constant usual regimen is to give methylprednisolone in a dose of involvement (diplopia)* Corneal involvement Absent or mild Moderate one gram intravenously for initial three days.This is followed by oral corticosteroids.If there is no *Intermittent diplopia occurs when the patient is fatigued or improvement after one to two weeks the patient should awakening in the morning. Inconstant diplopia occurs at extremes of gaze.Constant diplopia occurs both when the patient is looking undergo prompt surgical decompression . 1

Garima Agrawal1, D C Mehta2

Thyroid associated ophthalmopathy is common in patients with thyroid dysfunction. The present article reviews the current and future concepts in the management of thyroid associated ophthalmopathy. Many of the guidelines in the present article are based on the consensus statement of the European Group on Grave’s Orbitopathy. The present article was written after reviewing the articles on the net and journals as mentioned in the references. [J Indian Med Assoc 2016; 114: 24-7]

Key words : Thyroid associated ophthalmopathy, management.

whereas older patients, more than seventy years old, can develop severe, isolated muscle enlargement associated with compressive optic neuropathy . The shared auto-antigen may be the thyrotropin receptor or the insulin like growth factor 1 receptor. B cells act as antigen presenting cells and autoantibody producing cells. Genetic factors in Graves' ophthalmopathy remain poorly understood.Environmental factors play a major role in the development and progression of the ophthalmopathy. These include smoking as an important risk factor. Microbial infections have also been postulated as a risk factor .

cular involvement is common in patients with thyroid disease. In these patients the status of the thyroid is variable. The majority are hyperthyroid, some are hypothyroid while a few are euthyroid.In many it may be difficult to demonstrate any thyroid abnormality at all. Thus the management of the thyroid dysfunction and the threat to vision requires close co-operation between the ophthalmologist and the physician/endocrinologist. The present article reviews the current and future trends in the management of thyroid associated ophthalmopathy.

The present article was written after reviewing articles on the internet and the journals as mentioned in the references.It was kept in mind to include the recent studies and updates on the subject .The authors experience in treating patients of Thyroid associated ophthalmopathy (TAO) in the clinics was invaluable in writing the article.

Clinical Features : The clinical features include lid retraction,lid lag,proptosis, extra-ocular muscle involvement, optic neuropathy, conjunctival congestion and chemosis (Fig 1). The natural course of thyroid ophthalmopathy is variable.Usually there is an active phase that lasts for onetwo years followed by a plateau phase when the disease becomes stable and finally the inactive phase when there is remission.The remission is generally incomplete .

Pathogenesis : TAO is initiated by autoreactive Tcells that react with one or more antigens shared by the thyroid and the orbit.These T lymphocytes after reaching the orbit react with the shared auto-antigen and trigger a cascade of events.There is secretion of cytokines which cause proliferation of fibroblasts, expansion of adipose tissue and secretion of hydrophilic glycosaminoglycans from the fibroblasts.There is a resultant increase in orbital content which explains many features of the ophthalmopathy .

Diagnosis and Investigations : The diagnosis is certain in patients with bilateral ophthalmopathy and thyroid dysfunction. Thyroid dysfunction is evident by serum levels of T3,T4 and TSH. In those with doubt orbital imaging and measurement of thyrotropin receptor antibodies is warranted. Presence of high levels of serum thyrotropin receptor antibodies are highly specific and sensitive for thyroid associated ophthalmopathy. Orbital imaging with CT scan or MRI will reveal enlargement of the extra-ocular muscles with

1,2

Those individuals younger than forty years are considerably more likely to manifest orbital fat expansion related proptosis in the absence of muscle infiltration, M & J Institute of Ophthalmology, BJ Medical College, Ahmedabad 380016 MS (Ophthalmol), Assistant Professor MS (Ophthalmol), Professor and Director 1

5,6

straight ahead and when the patient is looking down

J INDIAN MED ASSOC, VOL 114, NO 4, APRIL 2016

Moderate to severe and active ophthalmopathy also requires treatment with glucocorticoids. The recommended regimen consists of twelve weekly infusions of methylprednisolone with a cumulative dose of 4.5 grams (500mg weekly for 6 weeks, then 250 mg weekly for 6 weeks) . Intravenous therapy should be given only with close monitoring (specially of liver function) in specialised centres . To minimise the risk of hepatotoxicity courses exceeding 8 grams are not recommended . Rare cases of severe and acute liver damage have been reported with the use of high doses of intravenous steroids . High dose oral glucocorticoids in a dose of 40mg or higher initially followed by tapering until withdrawal after 4-6 months are also used. They are a reasonable option in patients with liver disease . Patients should be closely monitored for other potential aspects of glucocoticoid therapy as high blood pressure, hyperglycaemia,gastric side-effects,infection and electrolyte abnormalities . Two randomised controlled trials have shown that intravenous therapy has a higher rate of favourable response as compared to oral therapy.Intravenous therapy is also well tolerated with reduced risk of development of cushingoid features.However a close watch on liver functions as mentioned above is mandatory . Orbital radiotherapy : Orbital irradiation may be used as an additional therapy.It has been found to be beneficial particularly when eye motility is impaired though it has been observed that patients with certain features, including exophthalmos, eyelid retraction, and soft-tissue changes, tend to have a poor response to treatment . Radiation is given in ten sessions over a two weeks period with a total cumulative dose of 10-20 Gy. It should be avoided in patients with diabetic retinopathy or severe hypertension (as may cause retinal damage)and in patients younger than 35 years of age (due to long term potential carcinogenic effects) .Combined treatment with glucocorticoids and radiotherapy has been found to be more effective than either treatment alone as suggested by data from randomised trials . Surgery : Orbital decompression surgery is required for sight threatening optic neuropathy and for sight threatening exposure keratopathy.Orbital decompression is indicated in sight threatening optic neuropathy if high dose glucocorticoids do not result in improvement in one to two weeks . It is also indicated in vision threatening exposure keratopathy which does not improve with supportive measures . Cosmetic surgery for Graves ophthalmopathy should be performed after the disease has been consistently inactive for at least six months.Here the order to be followed is orbital decompression followed by strabismus surgery followed by eyelid surgery .

CURRENT AND FUTURE TRENDS IN THE MANAGEMENT OF THYROID — AGRAWAL AND MEHTA 27

Other immunosupressive agents : Steroid sparing agents such as azathioprine ,50-150 mg/day or cyclosporin A, 5-7 mg/kg for 4-12 months may be used in the treatment of cases with persistent diplopia despite steroid therapy or those intolerant to steroids . 1

Recent Advances And Future Trends :

5,6,9

10-12

5,6

Rituximab is an anti CD20 monoclonal antibody that induces transient B cell depletion that modifies the active inflammatory course of thyroid associated ophthalmopathy . In an open label study Mario et al found that rituximab significantly decreased proptosis and inflammation in patients with active TAO. Etanercept is an inhibitor of tumour necrosis factor. Paridaens et al in a pilot study found etanercept to decrease inflammation and the clinical signs of Graves ophthalmopathy. 14,15

Conclusion : The management of thyroid ophthalmopathy requires a multidisciplinary approach involving the ophthalmologist and the endocrinologist. The above review gives the current recommendations in the management of this disease largely based on the consensus statement of the European Group on Graves’ Orbitopathy (EUGOGO) on management of Graves ophthalmopathy. Newer drugs as rituximab and TNF inhibitors await randomised controlled trials. They may well open a new paradigm in the management of this complex disorder in the near future. 5,6

REFERENCES 1 Luigi B, Laura TM — Grave’s ophthalmopathy. N Engl J Med 2009; 360: 994-1001. 2 Bednarczuk T, Hiromatsu Y, Inoue Y, Yamamoto K, Wall JR, Nauman J — T-cell mediated immunity in thyroid associated ophthalmopathy. Thyroid 2002; 12: 209-15. 3 Prabhakar BS, Bahn RS, Smith TJ — Current perspective on the pathogenesis of Graves’ disease and ophthalmopathy. Endocr Rev 2003; 24: 802-35. 4 Mourits MP, Prummel MF, Wiersinga WM, Koornneef L — Clinical activity score as a guide in the management of patients with Graves’ ophthalmopathy. Clin Endocrinol 1997; 47: 9-14. 5 Bartalena L, Baldeschi L, Dickinson A — Consensus statement of the European Group on Graves’ Orbitopathy (EUGOGO) on management of Graves' ophthalmopathy. Eur J Endocrinol 2008; 158: 273-85. 6 Bartalena L, Baldeschi L, Dickinson A — Consensus statement of the European Group on Graves’ Orbitopathy (EUGOGO) on management of Graves’ orbitopathy. Thyroid 2008; 18: 333-46. 7 Dolman PJ, Rootman J – VISA classification for Graves orbitopathy. Ophthal Plast Reconstr Surg 2006; 22: 319-24.

8 Kahaly GJ, Pitz S, Hommel G, Dittmar M — Randomized, single blind trial of intravenous versus oral steroid monotherapy in Graves’ orbitopathy. J Clin Endocr Metab 2005; 90: 5234-40. 9 Van Geest RJ, Sasim IV, Koppeschaar HPF — Methylprednisolone pulse therapy for patients with moderately severe Graves’ orbitopathy: a prospective, randomized, placebo-controlled study. Eur J Endocrinol 2008; 158: 229-37. 10 Marinó M, Morabito E, Brunetto MR, Bartalena L, Pinchera A, Marcocci C — Acute and severe liver damage associated with intravenous glucocorticoid pulse therapy in patients with Graves’ ophthalmopathy. Thyroid 2004; 14: 403-6. 11 Le Moli R, Baldeschi L, Saeed P, Regenburg N, Mourits MP, Wiersinga WM — Determinants of liver damage associated with intravenous methylprednisolone pulse therapy in Graves’ ophthalmopathy. Thyroid 2007; 17: 357-62.

12 Weissel M, Hauff W — Fatal liver failure after high-dose glucocorticoid pulse therapy in a patient with severe eye disease. Thyroid 2000; 10: 521. 13 Bradley EA, Gower EW, Bradley DJ — Orbital radiation for Graves ophthalmopathy: a report by the American Academy of Ophthalmology. Ophthalmology 2008; 115: 398-409. 14 Salvi M, Vannucchi G, Campi I — Treatment of Graves’ disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an open study. Eur J Endocrinol 2007; 156: 33-40. 15 El Fassi D, Nielsen HC, Hasselbalch HC, Hegedüs L — Treatment resistant, severe, active Graves’ ophthalmopathy successfully treated with B lymphocyte depletion. Thyroid 2006; 16: 709-10. 16 Paridaens D, van den Bosch WA, van der Loos TL, Krenning EP, van Hagen PM — The effect of etanercept on Graves’ ophthalmopathy: a pilot study. Eye 2005; 19: 1286-9.

Case Note

A RARE CASE OF KIMURA’S DISEASE OF CHEEK — MISHRA AND JOSHI

A rare case of Kimura’s disease of cheek 1

Kimura’s disease is a rare benign chronic inflammatory disorder of unknown cause that mostly presents as painless unilateral cervical lymphadenopathy or solitary/multiple masses in the head –neck region. Here, a case of swelling in cheek, anterior to parotid gland which was later found to be due to Kimura’s disease has been described. [J Indian Med Assoc 2016; 114: 28-9]

Key words : Kimura, eosinophilia, angiolymphoid hyperplasia, lymphadenopathy.

aberrant immune reaction to an unknown antigenic stimulus has been suggested, perhaps implicating a role for Candida albicans, but no formal demonstration has been made to date. It can be suggested that prolonged immunologic stimulation can lead to clonal lymphoid proliferation in occasional cases. Mast cells, a major source of interleukin 4 and 5, might play an important role in the pathogenesis of Kimura’s disease, by regulating IgE synthesis and orchestrating eosinophilic infiltration. However measurements of IgE levels were not done in this case. Other mechanisms postulated are trauma and persistent parasitic antigenic stimulation. The onset of KD is insidious and lesions are benign, following an indolent course, gradually increasing in size over years. The Fig 2 — Microphotograph Showing Extensive Sclerotic Areas Punetuated by Lymphoid prognosis is good and no malignant Follicles and Large Number of Eosinophils transformation has been reported. common. Localised initial regrowth can be managed with Diagnosis of KD is frequently difficult . A biopsy and/or surgical excision, other therapeutic options include radiation in excision of the involved lymph node or the lesion itself is cases refractory to medical and surgical therapy, systemic required for definitive histopathological diagnosis, and is often corticosteroids especially in frequent relapses or cases therapeutic as well. The histopathological picture is same complicated with nephritic syndrome . Cytotoxic agents, regardless of the site involved and is characterised by lymphoid cyclosporine and pentoxyphylline can also been tried. follicles formation with prominent germinal centres, infiltration of eosinophils, sometimes forming micro-abscesses, fibrosis, increased postcapillary venules and vascular proliferation. REFERENCES Vessels remain thin-walled with cuboidal endothelial cells. 1 Kimm HT, Szeto C — Eosinophilic hyperplastic Polykaryotic giant cells of the Warthin-Finkeldey type are a lymphogranuloma, comparison with Mikulicz's disease. Prof common feature. The role of fine needle aspiration cytology Chin Med Soc 1937; 7: 329. (FNAC) is for the diagnosis of recurrent lesions. 2 Kimura T, Yoshimura S, Ishikawa E — On the unusual Clinical differential diagnosis for KD include reactive granulation combined with hyperplastic changes of lymphatic tissues. Trans Soc Pathol Jpn 1948; 37: 179-80. lymphadenopathy, lymphoma, salivary gland tumour, nodal metastasis (breast, colorectal and nasopharyngeal cancer), 3 Larroche C, Bletry O — Kimura’s disease. Guillevin L, editor. lymphangioma, haemangioma and Mikulicz’s disease. O r p h a n e t E n c y c l o p e d i a , 2 0 0 5 . www.orpha.net/data/patho/uk_kimura.pdf : 1-3 (access 20). Although not diagnostic, CT and MRI can help in 4 Yuen HW, Gah YH, Low WK, Lim-Tan SK — Kimura’s distinguishing Kimura’s disease from other conditions and disease: a diagnostic and therapeutic challenge. Singapore delineating the extent of disease. Med J 2005; 46: 179-83. The treatment of Kimura’s disease is problematic. Surgical 5 Kohli A, Singh G — Kimura’s disease. JK Science 2008; 10: excision has been found to be curative although recurrence is 3

Mukesh Mishra , Sandhya Joshi

he first report of Kimura's disease (KD) was from China in 1937, in which Kimm and Szeto described 7 cases of a condition they termed “eosinophilic hyperplastic lymphogranuloma”. The disorder received its current name in 1948, when Kimura et al noted the vascular component and referred to it as an “unusual granulation combined with hyperplastic changes in lymphoid tissue”. The disease is endemic in Asia especially in China and Japan. There is a male predominance with a M/F ratio of 3.5 : 1 to 9 : 1 in most series reported. Kimura’s disease involves the skin, lymph nodes and salivary glands in the head –neck area and is reported to be associated with nephritic syndrome in approximately 15-19 % of cases. 1

CASE REPORT

A 47-year-old female, a native of Nepal, presented in ENT OPD at General Hospital, Dahod with a painless, slow growing left sided cheek swelling for 3 years.She complained of occasional itching over the lesion with disfigurement of the cheek. Examination — The swelling was ill-defined with no definite margins, non-tender, immobile, soft to firm in consistency in the subcutaneous plane anterior to the parotid region (Fig 1). Skin over the swelling was mildly darkened in colour. Clenching of the teeth would slightly demarcate the swelling which was not fixed to the underlying muscle. Compared to the right side of the cheek there was fullness on the left side. Intra-orally the mucosa was normal. No neck lymphadenopathy was noted. No other abnormality was detected. Investigations — Routine blood investigations revealed eosinophilia. A provisional diagnosis of soft tissur tumour was made.The patient was prepared for general anaesthesia and excision of the swelling was planned by external route. Treatment — A 8 cm long skin incision was made over the swelling at the level of an imaginary line connecting tragus

Fig 1 — Showing an Ill-Defined Swelling Auterior to the Parotid Region

to oral commisure. A subcutaneous yellowish-brown swelling of size 5x4x1 cm approximately with irregular margins was exposed, overlying but adherent to muscle and the parotid tissue. After careful dissection from the Wharton's duct, the lesion was excised in toto. Haemostasis was achieved. Wound was closed with a small drain which was removed on the 2nd postoperative day. Pressure dressing was applied. No postoperative facial nerve paresis was noted. The patient was put on tab cetirizine 10 mg once daily. Histopathology — Histopathological study of the specimen showed extensive sclerotic areas punctuated by lymphoid follicles and alarmingly large number of eosinophils even forming micro-abscesses. This picture is classical of KD (Fig 2, H&E x 20). Follow-up — Follow-up was done after 2 and 6 months. No recurrence of swelling was seen and fullness over the cheek had subsided.

Department of ENT, Government General Hospital, Dahod 389151 MS (ENT), Consultant ENT Surgeon MD (Anaesthesiol), Consultant Anaesthetist, Department of Anaesthesiology

DISCUSSION

The aetiology of this chronic disease is unknown. An

149-50.

Case Note

Joubert syndrome : a case report

A rare case of leukaemoid reaction in Plasmodium falciparum infection : a case report

P A Fazal Ghafoor1, Sajeer K T2, Jamaludheen C V3

Ashutosh Kumar1, Rashmi Kushwaha2, Vimala Venkatesh3, Mastan Singh4 Here is reported a child with developmental delay, hypotonia during infancy, rotator nystagmus, dysarthria and mental retardation who was diagnosed to have Jouberts syndrome at 8 years of age.

Haematological presentation of malaria is usually in the form of leucopaenia along with increased number of monocytes and macrophages. Rarely, cases have been reported in which initial presentation of malaria is in the form of leukaemoid reaction. No cases have been found on websearch from Indian subcontinent. Because of the apparent rarity of leukaemoid reaction in Plasmodium falciparum infection, the following case has been reported. [J Indian Med Assoc 2016; 114: 31-2]

[J Indian Med Assoc 2016; 114: 30 & 32]

Key words : Joubert syndrome, molar tooth sign, magnetic resonance imaging.

what may be described as “bat wing appearance.” Size of the posterior fossa was normal with cerebrospinal fluid filling the ventricular space. All these findings suggested Joubert syndrome.

oubert syndrome (JS) is an autosomal recessive neurodevelopmental disorder, which is characterised by the molar tooth malformation (MTM), a complex brainstem malformation that reflects aplasia or marked hypoplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles and a deepened interpeduncular fossa that is apparent on axial MRI at the midbrain–hindbrain junction . Clinically, classic JS is associated with neonatal hypotonia (loss of muscle tone), ataxia, developmental delay, mental retardation, and often neonatal apnoea/hyperpnoea (irregular breathing) and/or ocular motor apraxia (difficulties in initiating rapid horizontal eye movements or saccades) . Autistic features have also been reported as a relatively common component of JS .

DISCUSSION

2,3

4,5

CASE REPORT

An 8-year-old malnourished girl with motor and mental retardation presented with the complaints of inability to fix gaze, failure to gain weight and weakness and ataxia. She was the first child of a first degree consanguineous marriage. There was no history of similar illness in the family. Her past history disclosed developmental retardation. Examination — Major retardation was seen involving the gross motor system. She was able to sit without support by the age of one year and she could walk a few steps by herself by the age of two. Speech could be understood clearly when she was 5 years old. She had been a hypotonic and hypo-active baby all throughout her childhood, and had nystagmus in the form of rotatory eye movements noticed by her parents since she was a few months old. She was born as a full term vaginally delivered child with a birth weight of about 2.5 kg. She had dysarthria, rotatory nystagmus and gait ataxia.

Investigations — An Magnetic resonance imaging (MRI) brain study was done which revealed vermian agenesis. Isthmus was hypoplastic together with thickening and elongation of the superior cerebellar peduncles giving “molar tooth” appearance (Fig 1). Also, the shape of the 4th ventricle had been changed into

hepatosplenomegaly, both two fingers below the respective he majority of malaria patients at presentation have total costal margins. white blood cell (WBC) count in the normal range. Leucopaenia (WBC count < 4 × 10 /l) may affect up to 15% of Investigations — Peripheral smear and bone marrow patients. Rate of leucocytosis (WBC count >10 × 10 /l) in adults aspiration was done. Total leucocyte count was 19,600 range between 1 and 7%. Reportedly, malaria induced changes in the differential white cell count include neutropaenia, neutrophilia, immature neutrophils (left shift), neutrophil toxic granulation, lymphopaenia, lymphocytosis, atypical lymphocytes, monocytosis, eosinopaenia, posttreatment eosinophilia and leukaemoid reactions. The underlying mechanisms include a shift in neutrophils from the circulatory to the marginal pool to sites of inflammation, splenic localisation, serum lymphotoxic factors and intercurrent bacterial infections . Irving et al reported a case of a 4-year-old patient with Plasmodium falciparum infection. The blood picture was that of a leukaemoid reaction with severe anaemia and high total leucocyte count. Similar cases were reported by Soe et al and Captain James et al . Because of the difficulties of diagnosis posed by a leukaemoid picture in malaria and the rarity of Fig 1 — Microphotograph Showing Plasmodium Falciparum Gametocyte (Arrow) this finding, this case has been reported. It is possible that the increased haemolysis and the attending anaemia are cells/cmm. Differential count revealed 21% polymorphs, 63% responsible in certain cases for sufficient bone marrow lymphocytes and 4% cells of immature granulocyte series stimulation to cause this change . mainly myelocytes, 1% eosinophils and 11% monocytes. 9

Joubert syndrome was first identified by pioneering paediatric neurologist Marie Joubert and associates in 1969 in four siblings and one sporadic case that exhibited episodic hyperpnoea, abnormal eye movements, ataxia and mental retardation with agenesis of cerebellar vermis and dilatation of fourth ventricle in typical batwings configuration . Approximately 10% of individuals with Joubert syndrome have abnormal collections of cerebrospinal fluid in the fourth ventricle or the posterior fossa that resemble Dandy-Walker malformation. Worldwide around 200 cases of Jouberts' syndrome have been reported. In the syndrome midline structures of the brain stem have both anatomic and functional defects. Neuropathological studies reveal agenesis of the cerebellar vermis, malformation of several brainstem nuclei and dysplasia of structures at the pontomesencephalic junction. Extensive brain stem malformation could explain the oculomotor apraxia and hyperpnoea; anomalies of gracilie nuclei and solitary tract are thought to contribute to the abnormal respiratory pattern . The eye abnormalities observed in this disease usually wane off with age. The eye abnormalities observed in this disease include complete oculomotor apraxia in horizontal and vertical directions and ocular coloboma . Hypotonia and mental retardation are non-variable features of Joubert syndrome. Long term follow-up of the children with this disease reveals majority having severe mental and motor developmental impairments. Inheritance of this disease is said to be autosomal recessive. Recent studies have shown that it is a genetically heterogeneous disorder with one locus pointing to chromosome 9q .

Key words : Leukaemoid reaction, malaria, Plasmodium falciparum.

CASE REPORT

Platelet count was 84,000/cmm. Few nucleated red blood cells were also present. Plasmodium falciparum gametocyte and ring forms were present (Fig 1, Leishman stain, x 40). Haemoglobin was 8 g/dl. Reticulocyte count was reduced. Bone marrow smears were cellular with increased number of lymphocytes (41%), majority with large ‘activated’ morphology. Granulocytic precursors (40%) showed heavy toxic granules. Erythropoesis was normoblastic (19%). Megakaryocytes were present in normal number. Macrophages with phagocytosed brown pigment were seen in increased number. Smears also showed presence of Plasmodium falciparum gametocyte.

The striking structural defects of Joubert syndrome in imaging studies are dysgenesis of the isthmus (part of the brainstem between pons and inferior colliculus) which is seen as elongation and thinning of ponto-mesencephalic junction, and deep interpeduncular fossa; thickening of superior cerebellar peduncles; hypoplasia of the vermis characterised by incomplete lobulation and enlarged fourth ventricles; incomplete fusion of the halves of the vermis creating a sagittal cleft seen on coronal MRI planes. Combinations of the first three features produce the characteristic “molar tooth sign”

Department of Medicine, MES Medical College, Palachode 679338 MD (Gen Med), DM (Neurology), Associate Professor and Consultant Neurologist MD (Gen Med), Assistant Professor MBBS, DHSc (Public Health), MHSc (Public Health), Registrar 1

A 10-month-old female child presented with fever with chill and rigour since two days and progressively increasing pallor. Examination — The patient was anaemic and had

Department of Pathology, CSM Medical University, Lucknow 226003 MD (Pathol), Professor MD (Pathol), Assistant Professor MD (Microbiol), Professor of Microbiology MD (Microbiol), Professor and Head of the Department of Microbiology 1

(Continued on page 32) 30

J INDIAN MED ASSOC, VOL 114, NO 4, APRIL 2016

Her liver function test showed increased billirubin, increased aspartate and alanine transferase. Management and Follow-up — The patient was given injection artesunate 2.4 mg/kg body weight intravenously at diagnosis, then at 12 hours and 24 hours, then once a day for 24 hours. This was followed by artemisinin based combination therapy (ACT) consisting of artesunate and amodiaquine; 4 mg/kg body weight of artesunate and 10 mg base/kg body weight of amodiaquine was given once a day for 3 days orally in tablet form. Following treatment his peripheral smear was made at 6th day and 28th day after treatment and they showed complete disappearance of parasites. DISCUSSION

The blood stage of falciparum malaria may cause lifethreatening anaemia. The anaemia is typically normocytic and normochromic, with a notable absence of reticulocytes. Red blood cells are destroyed as parasites complete their growth cycle; although some parasites may be removed from erythrocytes as immature ring forms by phagocytic cells. Infected erythrocytes may also be phagocytosed by macrophages following opsonisation by immunoglobulins and/or complement components . Reticulocytopaenia has been observed in numerous clinical studies of malarial anaemia. This is due to an increased proportion of the erythroid prognitors in the G2 phase . Thrombocytopaenia is almost invariable in malaria and so 5

may be helpful as a sensitive but non-specific marker of active infection. Increased removal of platelets may follow absorption of immune complexes . Haematological presentation of malaria is usually in the form of leucopaenia along with increased number of monocytes and macrophages. Rarely, cases have been reported in which initial presentation of malaria is in the form of leukaemoid reaction. Such cases pose difficulties in diagnosis. It is possible that the increased haemolysis and the attending anaemia are responsible in certain cases for sufficient bone marrow stimulation to cause this change . 5

Case Note Bilateral non-arteritic anterior ischemic optic neuropathy (NAION) — a case report Asha R Prasad1, S P Jakhanwal2

Non-arteritic Anterior Ischemic Optic Neuropathy (NAION) is due to ischemia of the optic nerve head. This is one of the causes of blindness or seriously impaired vision among middle aged and elderly population. Ophthalmoscopic examination in active stage shows a sectoral disc swelling and peripapillary haemorrhage. We report a case of a 50 year old male who presented with complaints of some blurring of vision in right eye. Fundus examination had similar picture as described above. He underwent thorough ocular, systemic and haematological evaluation after which he was diagnosed to be suffering from Non-arteritic AION. Nocturnal hypotension was diagnosed to be the cause for his condition. While on treatment with steroids he developed similar picture in his fellow eye. Antimetabolites was then added to his treatment regime and continued for six months till his optic disc swelling subsided and disease progression was halted. Though his central vision remained as 6/9 and 6/6 respectively, his visual field showed marked altitudinal defects. The patient was followed for two years. No further deterioration of vision was seen but his field of vision remained impaired.

REFERENCES

1 Taylor WR, Widjaja H, Basri H, Ohrt C, Taufik T, Tjitra E, et al — Changes in the total leukocyte and platelet counts in Papuan and non Papuan adults from northeast Papua infected with acute Plasmodium vivax or uncomplicated Plasmodium falciparum malaria. Malar J 2008; 7: 259. 2 Irving KG, Kemp E, Olivier BJ, Mendelow BV — Unusual presentation of malaria as a leukaemoid reaction : a case report. S Afr Med J 1987; 71: 597-8. 3 Soe S, Tin S, Than S — Myeloid leukemoid reaction in malaria infection. Southeast Asian J Trop Med Public Health 1991; 22: 677-8. 4 James AR, George MR — Leukemoid Reaction due to Mixed Malarial Infection. NewJersey. Medical Service, Tilton General Hospital, Fort Dix, 1946: 283-7. 5 Weatherall DJ, Miller LH, Baruch DI, Marsh K, Doumbo OK, Casals-Pascual C, et al — Malaria and the red cells. Hematology 2002; 1: 35-57.

(Continued from page 30)

[J Indian Med Assoc 2016; 114: 33-5]

Key words : Non-arteritic Anterior Ischemic Optic Neuropathy, optic nerve head.

on-arteritic AION is characterised by visual loss associated with optic disc swelling and subsequently varying degrees of optic atrophy. Sometimes flame shaped haemorrhage is seen on the swollen disc or nearby neuroretinal layer. The incidence of AION is estimated to be 2.3 – 10.3 per 100.000 . Nocturnal arterial hypotension is found to have an important role in producing Non arteritic AION and most patients experience visual disturbances immediately on waking up in the morning. Hypotension causes hypoperfusion of optic nerve head . The blood supply to the anterior head of the optic nerve is mainly by the posterior cilliary arteries and it is these arteries which are affected thus producing ischemia of optic nerve head and causing nerve conduction defects (Fig 1). We report a case who observed sudden visual disturbances in one eye on waking up in the morning, followed by a similar observation in the other eye just after a month and a half. After all necessary investigations he was finally diagnosed to be suffering from bilateral NAION due to nocturnal hypotension.

soon after getting up this morning. Soon as he opened his eyes, he was momentarily only seeing scenes which had occurred the previous day, like his wife wearing a green sari and opening cupboard, which was a scene that had occurred the previous day. This was then followed by decrease in his clarity of vision in same eye.

on axial MRI or CT planes. Tecto cerebellar dysplasia and Dandy –Walker syndrome , two other situations which may be the source of confusion, also may accompany Joubert syndrome . 4

REFERENCES

1 Maria BL, Hoang KB, Tusa RJ, Mancuso AA, Hamed LM, Quisling RG, et al — ‘Joubert syndrome’ revisited: key ocular motor signs with magnetic resonance imaging correlation. J Child Neurol 1997; 12: 423-30. 2 Joubert M, Andermann F — Familial agenesis of the cerebellar vermis: a syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation. Neurology 1969; 19: 813-25. 3 Boltshauser E, Isler W — Joubert syndrome: episodic hyperpnea, abnormal eye movements, retardation and ataxia, associated with dysplasia of the cerebellar vermis. Neuropaediatrics 1977; 8: 57-66. 4 Maria BL, Boltshauser E, Palmer SC, Tran TX — Clinical features and revised diagnostic criteria in Joubert syndrome. J Child Neurol 1999; 14: 583-90. 5 Holroyd S, Reiss AL, Bryan RN — Autistic features in Joubert syndrome: a genetic disorder with agenesis of the cerebellar vermis. Biol Psychiat 1991; 29: 287-94. 6 Joubert M, Eisenring JJ, Robb JP, Andermann F — “Familial agenesis of the cerebellar vermis: a syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation”. Neurology 1969; 19: 813-25. 7 Yachnis AT, Rorke LB — Neuropathology of Joubert syndrome. J Child Neurol 1999; 14: 655-9.

CASE REPORT

Fig 1 — MRI of Brain Showing Molar Tooth Sign 8 Tusa RJ, Hove MT — Ocular and occulomotor signs in Joubert syndrome. J Child Neurol 1999; 14: 621-7. 9 Chance PF, Cavalier L, Satran D, Pellegrino, Koeing M, Dobyns WB — Clinical and genetic aspects of Joubert and related syndromes. J Child Neurol 1999; 14: 660-6.

A 50 year old man presented with Fig 1 – Blood supply of the optic nerve head blurring of vision in right eye since He was not a known diabetic or hypertensive. The only drug morning. He narrated a peculiar symptom which he had observed patient was taking was Allopurinol because of hyperuricaemia. His blood pressure was 110/88mmHg. There was no past ocular history or relevant family history, but personal history revealed Department of Ophthalmology, Tata Main Hospital, Jharkhand 831001 that he was a smoker. MS (Ophthalmol), Specialist MS (Ophthalmol), Head of the Department & Sr Specialist

J INDIAN MED ASSOC, VOL 114, NO 4, APRIL 2016

BILATERAL NON-ARTERITIC ANTERIOR ISCHEMIC OPTIC NEUROPATHY (NAION) — PRASAD AND JAKHANWAL

On examination his visual acuity was 6/18 in Right eye (RE) and 6/6 in Left eye(LE). He had a slight brightness perception defect and an afferent papillary defect in right eye. Ophthalmoscopically there was blurring of right disc margin with single splinter hemorrhage in peripapillary region (Fig 2). Humphrey’s visual field demonstrated marked peripheral field defect with visual field reduced to tubular vision in right eye whereas visual field in left eye was normal (Fig 3).Differential diagnosis was optic neuritis , multiple sclerosis, neuromyelitisoptica. MRI of the brain and orbits was normal. A diagnosis of optic neuritis was made and he was given Pulse Methyl prednisolone 250 mg four times a day for 4 days; followed by oral prednisolone 40mg per day for 14 days. Symptoms did not improve significantly but disc oedema subsided. A month and a half later patient started observing similar disturbance in visual acuity and clarity in left eye. Similar sectoral disc oedema was seen in this eye also. Visual acuity was 6/9. Pupils were sluggishly reacting to light in both eyes and right eye now showed disc pallor. On general examination there was no pallor or icterus or palpable lymph nodes. Pulse was 84/min regular and blood pressure was 120/78mm Hg. Examination of CVS, respiratory system and abdomen was normal. Thorough neurological

evaluation was done. There was no history or symptoms to suggest any cranial nerve involvement. There was no motor or sensory impairment or cognitive decline. Higher functions were normal. Motor system showed normal bulk and tone and grade 5 powers in all four limbs. Motor nerve conduction of median nerve, ulnar nerve, peroneal nerve, tibial nerve and fascial nerve were normal. Abdominal reflexes were present and plantars was downgoing. Sensory system was normal. There were no cerebellar signs. Rhomberg’s test was normal. Skull and spine was normal. Visual Evoked Potential showed bilateral optic nerve dysfunction. Hematological reports showed Hb 18.2gm%, Platelet count 16700/cu mm. WBC differential – Neutrophils – 82%, Lymphocytes 15%, ESR 20mm at end of one hour.hr. CSF examination showed sugar 63mg%, protein 26mg%, WBC – 4 lymph, RBC normal. Faeces examination showed no ova or cyst. MCV-81.8fl; MCH- 28.1pg; MCHC-34.3 g/dl; S creatinine 0.9mg%; TSH 2.30Uiu/ml; Fasting blood sugar 99mg%; Postprandial blood sugar 103mg%; Serum Sodium-140m mol /L; Serum Potassium 3.3m mol/L; Cholesterol 252mg% ; CRP 30.3ug/l , ANA was negative. A nonreactive fluorescent treponemal antibody absorption test and a normal tuberculin skin test were present. He was started Azathioprim tablet 50 mg per day soon after involvement of second eye, and adviced to check haemoglobin, total count and platelet count once monthly, while on Azathioprim, and to stop the medicine if Hb<8mg%; total count <4000/cu mm platelet count < 100,000/cu mm. Azathoprim and Prednisolone was continued for 6 months and steroid was gradually tapered off. Atorvastatin 10 mg per day was given and he was advised low fat diet and low cholesterol diet. Disc oedema was seen to subside in 3 weeks. Both eyes showed disc pallor (Fig 4) though Visual acuity remained as 6/9. Improvement from initial loss Right eye Left eye of field of vision in right eye was seen and Fig 2 – Blurring of right disc margin with splinter hemorrhage while disc Humphrey’s visual field testing showed an margins of Left eye is normal altitudinal field defect in both eyes typical for NAION was seen (Fig 5). He was followed up till 10 years after stopping the medicine and was found to be stable. Because of the persisting inferior fields defects patient faced difficulty in walking reading and dressing up and was compelled for a compromised life style.

6,7

Right eye Left eye Fig 3 – Visual field of Right eye showing almost tubular vision while visual field of left eye is normal

atherosclerosis where nocturnal hypotension may act as final 4 Sevilla K, Groggel G — Anterior ischemic optic neuropathy insult leading to NAION . On both occasions our patient as a complication of hemodialysis. Am J Kidney Dis 1986; 8: experienced symptoms on waking up in morning. He was found 61-636 to have a marginally high cholesterol level and he was also a smoker which could have added to the hypoperfusion of nerve head by causing vasoconstriction. Patients with small disc have an anatomical predisposition for NAION as the Initial oedema compromises circulation producing further neuronal damage , but in our patient the disc appeared to be fairly normal size and he was emmetropic. About 15% of patients experience NAION in the second eye. Involvement of second eye is sequential and never simultaneous and visual loss usually stabilizes in few days . Decompression trials have Right eye Left eye been tried to salvage vision in the fellow eye . The disc Fig 4 – Pallor of both optic disc swelling and hemorrhage ultimately resolves with residual optic atrophy. Many of these patients are left legally blind. Unfortunately our patient was among them where of a bilateral involvement was present but probably with our treatment some good functional vision could be salvaged in both eyes. NAION produces an ischemic insult in the nerve head which inturn leads to release of vascular endothelial growth factor (VEGF). This causes rapid and reversible increase in vascular permeability and vasogenicedema of the affected nerve head. This edema cause compression and infarction of previously affected part of optic nerve and create a sort of compartment syndrome. Recent case reports have described a significant improvement in visual acuity and visual field in patient treated with intravitrealBevacizumab an anti vascular growth factor agent(Anti-VEGF) . Intravitreal bevacizumab may be a boon in halting the progression of visual field loss and improve the chances of preventing blindness, We also considered the possibility of an Right eye Left eye inflammatory optic neuropathy and therefore initiated Fig 5 – Altitudinal field defects in both eye an evaluation for possible inflammatory causes but all Laboratory testing were within normal limits. A Blood pressure 6 Johnson MW, Kincaid MC, Trobe JD — Bilateral retrobulbar of 110/88 mmHg, elevated cholesterol level and smoking habit optic nerve infarctions after blood loss and hypotension. A led us to a diagnosis of NAION which was confirmed by a repeat clinicopathological case study. Ophthalmology 1987; 94: 1577-84. visual field after 2 weeks of involvement of second eye. An 7 Jaben SL, Glaser JS, Daily M — Ischemic optic neuropathy Altitudinal defect was seen in both eyes and this feature is following general surgical procedures. J diagnostic of NAION. A second attack of NAION in same eye is ClinNeuroophthlmol 983; 3: 239-44. unlikely and no further deterioration of vision was seen in the 8 Hayreh SS, Joos KM, Podhajsky PA — Systemic diseases patient even until 10 years of follow up. 8

ACKNOWLEDGEMENT

DISCUSSION

Non-arteritic AION usually occurs spontaneously and is known to occur following acute hypotension . Sevilla et al reported cases of NAION secondary to hypotension episodes related to hemodialysis, rapid correction of malignant hypertension and systemic hypovolaemia .Chronic hypoperfusion of small end arterial blood vessels, that is the posterior ciliary vessels that supply the optic nerve head, may occur in blood loss during surgical procedures and can predispose to NAION . It has been hypothesized that if an optic nerve head has been rendered vulnerable to ischemia by various predisposing factors such as aging, hypertension, diabetes, hypercholesterolaemia,

We are thankful to Lt. Gen Dr. G. Ramdas (GM, Medical Services) and Dr DP Samaddar (CIMS) of Tata Main Hospital for their perpetual encouragement and guidance in every clinical activities.

REFERENCES

1 Hayreh SS — Ischemic Optic Neuropathy. Indian J Ophthalmol 2000; 48: 171-9,1. 2 Hayreh SS — The blood supply of the optic nerve head and the evaluation of it- Myth and Reality. Prog Retina Eye Res 2001; 20: 563-93 3 Hayreh SS, Podhajsky PA, Zimmerman B — Role of nocturnal arterial hypotension in optic nerve head ischemic disorgders. Ophthalmologica 1999; 213: 641-7 4 Hayreh SS. Blood flow in the optic nerve head and factors that may influence it. Prog Retina Eye Res 2001; 20: 595-624.

associated with nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol 1994; 18: 766-80. Beck RW, Servais GE, Hayreh SS — Anterior ischenmic optic neuropathy-IX . Cup -to –disc ratio and its role in pathogenesis. Ophthalmology 1987; 94: 1503-8. Beri M, Klugman MR, Kohler JA, Hayreh SS — Anterior ischemic optic neuropathy VII. Incidence of bilaterality and various influencing factors. Ophthalmology 1987; 94: 10208. Newman NJ, Scherer R, Langenberg P, Kelman S, Feldon S, Kaufman D, et al — The fellow eye in NAION; Report from the ischemic optic neuropathy decompression trial follow up study. Am J Ophthalmol 2002; 134: 317-28. Hosseini H, Razeghinejad MR — Anterio Ischemic Optic Neuropathy after intravitreal injection of bevacizumab.J Neuroophtalmol 2009; 29: 160-1.

SUPPLEMENT Branch Notes CUM CME, Topic: Revascularization Strategies in Unprotected Left Main Coronary Artery Critical Lesions: Is there a Paradigm Shift ? by Dr. K.P. Balakrishnan, MD, DM, FICC, HOD, Dept. of Cardiology, KIMS-Alshifa Hospital, Perinthalmanna. On 266-2016: Observation of INTERNATION DAY AGAINST DRUG ABUSE & ILLICIT TRAFFICKING. Press Meet at Calicut Press Club reg. Doctors’ day celebration on 1st July 2016. IMA Cochin Branch — 1stJune, 2016 Karuthal Cancer Detection Camp in BPHC Cheranalloor. On 11th June IMA Cochin Special CME on Bariatric Surgery. IMA Lagoon Nite.

IMA Badagara — The activities of May was evaluated by Dr.K.M.Subhash and Dr.C.Vijayaraghavan.World environment day activities were planned for June 6th. Doctors day to be celebrated on July 1st. The program is to be charted out later. Ifthar sangamam was decided to be held on 19th, Sunday. CME program “BASICON 2016” on 05-06-2016 : A one day CME Program “BASICON 2016” for General Practitioners was held on 05-06-2016 at Dazzle Banquet Hall,Vadakara.The program was organized by Ceeyam Academy in association with IMA –AMS. There was good participation with nearly 150 delegates attending the program. SWC meeting at Thalassery on 05-06-2016 : IMA Badagara actively participated in the SWC meeting held on 05-062016 at Thalassery.The President Dr. M. Muraleedharan, Dr. P.M.Saleem, Dr. C.Vijayaraghavan and Dr. K. M. Abdulla attended the meeting and actively participated in the discussions. World Environment Day was observed by IMA Badagara on 06-06-2016 at IMA Hall at 8 pm. After the program, Saplings were planted at the IMA Hall compound to observe the Environment Day. IMA Badagara organized an ‘Ifthar Sangamam’ on 19-06-16 at IMA Hall. IMA Perinthalmanna Branch — On 01.06.2016 : In connection with ‘Pravesanotsavam’, IMA Perinthlmanna Branch donated school kits for 40 tribal inmates of Sai Snehatheeram Boys Hostel on 1st of June, 2016. IMA also handed over Rs 10,000 to the hostel authorities. On 05.06.2016 the occasion of ‘World Environment Day’ WIMA members distributed tree saplings and also planted some fruit tree saplings at the District Hospital premises. IMA Perinthalmanna branch celebrated ‘World Blood Donor Day’ on 14th June, 2016 at the Perinthalmanna Blood Bank Auditorium. IMA Perinthalmanna branch members actively participated in ‘World Yoga Day’ observed on 21st June, 2016. Doctors Day to be celebrated on July 1st, 2016. As a part of ‘Drug Abuse and Anti-narcotic Day’, WIMA Perinthalmanna arranged a talk for students at Govt. Higher Secondary School, Perinthalmanna on 27th June, 2016. As a part of ‘Drug Abuse and Anti-narcotic Day’, WIMA Perinthalmanna arranged a class for students of CCST College, Karalmanna on 28th June, 2016. It celebrated Doctor’s Day along with Ifthar Meet on 1st July 2016. The program was a family get together of IMA Perinthalmanna branch members. IMA Kozhikode Branch — On 5-6-2016: world environmental day: Planting Trees at IMA Premises. Medical Camp for Police Force at Police Club, Kozhikode in association with MIMS & BMH . State Working Committee meeting at Thalassery. President, Secretary and other State leaders are attended. On 12-6-2016: Medical Camp for Police Force at Police Club, Kozhikode in association with MIMS & BMH . On 15-6-2016: IMA AMS CME, 75 members participated in the CME. Topic: A Nephrologists perspective on Hypertension by Dr. S. Vinugopal, Consultant Nephrologist, Kozhikode. On 166-2016: IMA District Task Force MEET at IMA Hall, Kozhikode. On 18-6-2016: IMA MBS family meet. On 19-62016: Medical Camp for Police Force at Police Club, Kozhikode in association with MIMS & BMH. On 23-6-2016: IMA GB

21st June International Yoga Day at General Hospital Ernakulam, 18th June. On 26th June IFTHAR meet at IMA. 29th June Special CME. General body meeting with CME was conducted in association with Indian Association of Psychiatry on recent advances in psychiatry. Presented ‘Ethics Pearls’ in Monthly meeting by Dr. Joy Joseph. Conducted three CMEs altogather in the month of June. Advances in Bariatric Surgery, Medicine, Science and Law. Cochin Clinical Society Meeting at Sunrise Hospital. Yoga day celebration and various activities by WIMA. IMA Kunnamkulam Branch — In June 3rd, connection with WORLD ENVIRONMENT DAY, IMA Kunnamkulam in association with WIMA conducted a program at adopted IMMNUEL LP SCHOOL, Chittanjoor. IMA donated Waste Baskets and Tree saplings to the school. Workshop for the volunteers of ACCIDENT CARE & TRANSPORT SERVICE(ACTS) of Thrissur District. Doctors Day to be celebrated on July 1st. CME and Ethical pearls for the month of June was discussed. In June 22nd, IMA Kunnamkulam and Police Department of Kunnamkulam division conducted First Aid Class and Drug Abuse and Traffic Accidents to the students of Vivekananda College Kunnamkulam. IMA Kuthuparamba Branch — Celebrating Doctors' Day on 1st July, 2016 and in the evening program began with an ‘Iftar’ party which was well attended by the IMA family and guests.

JIMA Guidelines for Authors Illustrations— Graphs, charts, diagrams or pen drawings must be drawn by professional hands in Indian ink (black) on white drawing paper. In case of x-ray, miniature photoprints should be supplied. Photographs should be supplied in high quality glossy paper not larger than 203 mm x 254 mm (8"x 10"). In case of microphotograph, stains used and magnification should be mentioned. Each illustration should bear on its back the figure number and an arrow indicating the top. All illustrations should be black and white and should be submitted in triplicate with suitable legends. References— References should be numbered in the order in which they are first mentioned in the text. The full list of references at the end of the communication should be arranged in the order mentioned below (names and initials of all authors and/or editors up to 6; if more than 6, list the first 6 followed by et al): Reference from journal : 1 Cogo A, Lensing AWA, Koopman MMW, Piovella F, Sivagusa S, Wells PS, et al —Compression ultrasonography for diagnostic management of patients with clinically suspected deep vein thrombosis: prospective cohort study. BMJ 1998; 316: 17-20. Reference from book : 2 Handin RI— Bleeding and thrombosis. In: Wilson JD, Braunwald E, Isselbacher KJ, Petersdorf RG, Martin JB, Fauci AS, et al editors—Harrison's Principles of Internal Medicine. Vol 1. 12th ed. New York: Mc Graw Hill Inc, 1991: 348-53. Reference from electronic media : 3 National Statistics Online—Trends in suicide by method in E n g l a n d a n d Wa l e s , 1 9 7 9 - 2 0 0 1 . www.statistics.gov.uk/downloads/theme_health/HSQ 20.pdf (accessed Jan 24, 2005): 7-18. Only verified references against the original documents should be cited. Authors are responsible for the accuracy and completeness of their references and for correct text citation. The number of reference should be kept limited to 20 in case of major communications and 10 for short communications. Dual publication : If material in a submitted article has been published previously or is to appear in part or whole in another publication, the Editor must be informed. Forwarding letter : The covering letter accompanying the article should contain the name, complete postal address along with e-mail identity of one author as correspondent and must be signed by all authors. The correspondent author should notify change of address, if any, in time. Declaration : A declaration should be submitted stating that the manuscript represents valid work and that neither this manuscript nor one with substantially similar content under the present authorship has been published or is being considered for publication elsewhere and the authorship of this article will not be contested by any one whose name (s) is/are not listed here, and that the order of authorship as placed in the manuscript is final and accepted by the co-authors. Declarations should be signed by all the authors in the order in which they are mentioned in the original manuscript. Matters appearing in the Journal are covered by copyright but no objection will be made to their reproduction provided permission is obtained from the Editor prior to publication and due acknowledgment of the source is made.

Communications intended for publication should be sent to the Editor, Journal of the Indian Medical Association (JIMA). JIMA will consider manuscripts prepared in accordance with the Vancouver style1. Articles are considered for publication on condition that these are contributed solely to JIMA, that they have not been published previously in print and are not under consideration by another publication. In the selection of papers and in regard to priority of publication, the opinion of the Editor will be final. The Editor shall have the right to edit, condense, alter, rearrange or rewrite approved articles, before publication without reference to the authors concerned. Authorship: All persons designated as authors should qualify for authorship. Authorship credit should be based only on significant contributions to (a) conception and design, or analysis and interpretation of data; and to (b) drafting the article or revising it critically for important intellectual content; and on (c) final approval of the version to be published. Conditions (a), (b) and (c) must all be met. Authors may include explanation of each author’s contribution separately. Manuscript and CD : Scripts of articles should be typewritten, double-spaced on one side of A4 size paper with at least 2.5 cm margin at the top and on left hand side of the sheet and should be submitted in triplicate. Also sending CD in Microsoft Word (Window) is a must. Manuscripts not accepted for publication will not be returned to the authors. Authors should keep one copy of their manuscripts for reference. Separate pages should be used for different sections. Title page— The title page should include the title of the article which should be concise but informative, name(s) of author(s) with his/her (their) academic qualification(s) and designation(s), and complete postal address including pin code of the institution(s) to which the work should be attributed. Abstract— The 2nd page should carry an abstract of no more than 250 words and should contain the purposes of the study or in-vestigations, basic procedure, main findings and their implications along with Key words. Text— The text of Originals and Papers should conform to the conventional division of abstract, introduction, material and method, observations, discussion and references. Other types of articles such as Practitioners’ Series, Case Notes, Current Topics, GP Forum, etc, are likely to need other formats. Statistical evaluation—Description of the statistical methods used should either be given in detail in the “material and method” section of the article or supportive reference may be cited. Abbreviations— Standard abbreviations should be used and be spelt out when first used in the text. Abbreviations should not be used in the title or abstract. Units of measurement— Metric units should be used in scientific contributions. If the conventional units or SI units were actually followed in measurements that should be given in parentheses. Drugs— The generic names of the drugs (and not proprietary names) including dose(s), route(s) and period of administration should be mentioned. Length of manuscripts— For Originals and Papers, Practitioners’Series, Preliminary Report, GP Forum and Current Topics: Maximum 2000-2200 words, 2-3 figures, and/or 2-4 tables, for Case Notes: Maximum 800 words, 2 figures, 1 table, for Letter to the Editor: 300-500 words. Tables— Tables should be simple, self-explanatory and should supplement and not duplicate the information given in the text.

— Hony Editor JIMA, 53, Sir Nilratan Sarkar Sarani (Creek Row), Kolkata - 700014 Phone : (033) 2236-0573, 2237-8092, Fax : (033) 2236-6437 E-mail : jima1930@rediffmail.com

April 2016 JIMA Advertiser

JOURNAL OF THE INDIAN MEDICAL ASSOCIATION: IMA House, 53 Sir Nilratan Sarkar Sarani (Creek Row), Kolkata - 700 014 Phones: (033) 2236-0573, 2237-8092, Fax: (033) 2236-6437, E-mail : jima1930@rediffmail.com, Website: www.ejima.in ; www.ima-india.org, www.ima-india.org/ejima Head office: Indian Medical Association, IMA House, Indraprastha Marg, New Delhi - 110 002 Telephones: +91-11-2337 0009, 2337 8680, Fax: +91-11-2337 9470, 2337 0375, Telegram: INMEDICI, New Delhi - 110 002, Email: hsg@ima-india.org; Website: www.ima-india.org

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APRIL 2016

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