aster medical journal

Volume 2 Issue 1

January-March 2015

Aster Medical Journal

Lead ArticlePediatric Critical Care : The Past & Present

ReviewsMetabolic SyndromeUnder addressed neurocognitiveissues in neurological disorders

Case Reportsn-butyl 2 Cyanoacrylate Embolization of CongenitalRenal ArteriovenousMalformationLaparoscopic Resection ofLarge Jejunal GIST

Medical ImageCarotid Body Tumor

Medical History Hemodialysis– an Overview

PatronDr. Azad Moopen

Editorial BoardEditor-in-ChiefDr. Anil Kumar R

EditorsDr. PC AlexanderDr. V JayakrishnanDr. Anjali KaleDr. Mayadevi KurupMs. Gracy MathaiDr. Suresh G NairDr. Dilip PanikarDr. Narayanan Unni VDr. Vijayamohan S

Associate EditorsDr. Iyoob AliDr. Vivek Radhakrishnan SDr. Raja Sekhar Varma

Assistant EditorsDr. Bibi DhananDr. Mustafa JaneelDr. Prakahs Nair

International Editorial AdvisorDr. Shelby Kutty

PublisherDr. Harish PillaiOn behalf of Aster DM Healthcare Pvt. Ltd.

Address for correspondence:Dr. Anil Kumar REditor-in-Chief, Aster Medical Journal,Aster Medcity, South Chittoor P O,Cheranelloor, Kochi 682 027, Kerala, India. Tel: +91 484 6699999 E-mail: [email protected]

Aster Medical Journal 2015Vol. 2 - Issue 1 CONTENTS

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Copyright © 2015, Aster DM Healthcare Ltd. All rights reserved.No part of this publication may be reproduced or transmitted in any form or by any means,electronic or mechanical, without written permission from the Editor-in-Chief.

Disclaimer: This Aster Medical Journal is published by Aster DM Healthcare Ltd. The views expressed in the journal are those of the authors and may not necessarily comply with Aster policy. This journal follows guidelines on editorial independence and the code on good publication practice. This journal is intended for medical professionals and is provided without warranty, express or implied. Statements in the journal are the sole responsibilities of their authors. Acceptance of advertising does not implyendersement. Though care has been taken to ensure accuracy and factuality of content, errors may creep in and the users are advised to verify any information they may choose to rely on.

For private circulation only.

1. Editorial

2. Lead Article Pediatric Critical Care : The Past & Present Rajappan Pillai

3. Reviews (a) Metabolic Syndrome Purnima K (b) Under addressed neurocognitive issues in neurological disorders Sandhya Cherkil

4. Case reports (a) n-butyl 2 Cyanoacrylate Embolization of Congenital Renal Arteriovenous Malformation Krishna Prasad BP, Vijay Jayakrishnan, Kishore T A, Narayanan Unni (b) Laparoscopic Resection of Large Jejunal GIST Iyoob V A, Shailesh C, Nanda K

5. Medical Image Carotid Body Tumor Krishna Prasad BP, Vijay Jayakrishnan, Swati C, Shilpa R, Zeeshan L, Brijesh R, Vandana S

6. Medical History Hemodialysis – an Overview Vinod Kumar K, V.N Unni

Editorial

The first issue of Aster Medical Journal 2015 comes out with Paediatric Critical Care as the lead article. This subspecialty was always cold shouldered till recently. Even when neonatal ICU care improved, paediatric critical care was kept on the backburner in many institutions. But things have changed for the better and this subspecialty is really growing in leaps and bounds, resulting in better outcomes for sick children. Dr Raj Pillai takes us through this journey.

Metabolic Syndrome is a common public health problem and contributes greatly to the increasing heart disease in society. Dr Purnima has reviewed this topic in detail and gives us guidelines on how to manage this condition. Neurocognitive problems are often ignored or never identified till late. Dr Sandhya has reviewed this issue comprehensively in this issue.

Two case reports - one from interventional radiology and the other from Surgical gastroenterology- shows us how minimally invasive procedures can reduce patient discomforts and at the same time ensure good clinical outcomes. In the section of Medical history, the nephrology team from Aster Medcity gives us an overview of how haemodialysis developed over the decades.

The future issues of Aster Medical Journal will be incorporating articles from all sister Aster institutions and thus AMJ will evolve into an Umbrella journal for the Aster family. We are working towards making the AMJ a standard indexed journal.

DR ANIL KUMAR

Aster Medical Journal - 2015 Vol. 2 - Issue 1

6

Pediatric Critical Care : The Past & Present

Rajappan Pillai. MD (Peds).Consultant Pediatric Intensivist, Aster Medcity, Kochi

Paediatric critical care is a young speciality which is well recognised only since the last two decades. Paediatric sub specialities have grown leaps and bounds over the last few decades and are challenging the frontiers of health care. The Critically ill children of these subspecialities raised the need for Paediatric critical care medicine. The speciality has grown with input from Adult Intensive Care, Paediatric Anaesthesiology, Neonatology and Paediatric general and cardiac surgery. Paediatric intensive care team currently plays a pivotal role in delivering care for all hospitalised sick children and has improved the outcome of all types of medical and surgical conditions.

The Past The Polio epidemics of 1930s led to the development of adult intensive care units1 where respiratory support was provided with “ Iron lungs” to patients in respiratory failure. Children admitted to these units had a higher mortality than adults. In 1950s, Neonatologists in their newly formed Neonatal intensive care units (NICU) gained experience treating babies with Hyaline membrane disease. Understanding of mechanical ventilation improved with increasing use of Continous positive pressure ventillation (CPAP) in NICU. The practices and protocols in neonatal intensive care improved significantly. Concurrently, Paediatric anaesthesia was increasingly recognised as a separate speciality in the anaesthetic world. The knowledge and understanding of physiology of a sick child improved with this. Further, the skills and practices in the field of Paediatric anaesthesia became more refined. The advancements in all these specialities contributed to better understanding and care of postoperative children. The Paediatric surgeons supported by the anaesthetist performed more and more complex surgeries. Children’s wards were not equipped to look after children postoperative. This lacunae was overcome by cohoring postoperative children and

allocating dedicated medical and nursing staff for their care.These wards progressed to become the future paediatric intensive care units.

The first pediatric ICU was established in Europe was by Goran Hugland in 1955 at Children’s hospital of Goetrburg in Sweden1. In the US, John Downes opened a pediatric ICU (PICU) at Children’s Hospital of Philadelphia in 19672. Over the next few decades, hundreds of PICUs was established in academic institutions and children’s hospitals across Europe and North America.

The Paediatric anaesthetists equipped with better understanding of principles of paediatric physiology and pharmacology gained from the operating rooms were instrumental in establishing the Paediatric intensive care units. But they lacked a more broad based pathophysiologic approach embracing nutrition, infectious diseases and metabolic issues. This raised a need for developing a Paediatric intensive care training programme. This training aimed at imparting paediatric skills to the anaesthetist and anaesthetic skills to the paediatrician. Fellowship and training programmes was started in 1970s to address this issue1. The Hospital for Sick Children in Toronto, Children’s Hospital of Philadelphia, Children’s Hospital of Boston amongst the earliest hospitals to start the Fellow ship programme in the US.

The Society of Critical Care Medicine recognised Paediatric critical care as a separate section in 1981. The American academy of paediatrics created a section on critical care in 19841. The first comprehensive textbook “ Textbook of Paediatric Intensive Care” was introduced by Mark Rogers in 1987. The first and only journal “ Paediatric critical care medicine “ was established in July 20001.

In India, Paediatric critical care is a rapidly growing speciality .The number of paediatric critical care units are limited given the large paediatric population of the country. The first organised Paediatric intensive care unit was established in 1991 at Kanchi Kamakoti Child’s Trust Hospital, Chennai, Tamil Nadu3.

Lead Article

Address for correspondence:Dr. Rajappan Pillai. MD (Peds).Consultant Pediatric Intensivist, Aster Medcity, KochiE-mail: [email protected]


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The “Iron lung” ICUs

A PICU cubicle at ASTER Medcity

Indian academy of Paediatrics with an aim to promote Paediatric critical care established IAP Intensive Care Chapter in 19984. Currently this chapter has more than 500 members. The first national congress of paediatric critical care was held in 1998 at Nagpur4. The chapter has established guidelines for PICU and training programs. Basic Paediatric intensive Care Certificate Course (fellowship) has been ongoing since 2002 in collaboration with ISCCM (paediatric section)4. This programme is currently offered by 21 units in the country. A DNB in Paediatric critical care is offered by National board since January 2007. A DM in paediatric critical care programme is also offered by PGI Chandigargh.

Journal of Paediatric Critical Care (JPCC) is a peer reviewed quarterly journal published by the the paediatric Intensive Care group of Indian Academy of Paediatrics4.

The Present The paediatric intensive care units have been established and providing high quality care in many of the large Indian cities.The infrastructure and

availability of equipments are in par with global standards.These units are capable of delivering entire spectrum of Pediatric critical care services. However, rural India and second tier cities still lags behind in the availability of skills and competencies to manage a critically ill child. Children are often transferred to larger cities for ongoing care. There is virtually no specialized paediatric team available for transport of a critically ill child. The ambulances available are predominantly customised to adult patient needs.

Availability of Paediatric intensivist round the clock can be ensured only in few centers and training institutions. A critically ill child is often managed in a peripheral hospital by a paediatrician with inputs from the anaesthetist. The nursing manpower with Paediatric intensive care training is limited. IAP

intensive care chapter have recently initiated training programmes to address this issue. Infection control and medication safety practices have received the due focus only in recent past. The escalating cost of intensive care is a serious challenge in delivery of critical care in India.

Last decade witnessed major advances in understanding of disease process in children. Newer technologies were introduced which helped in better managmnet and monitoring of sick children. Guidelines and protocols were introduced to streamline management which had a direct impact on care and outcome of sick children. Some of the high impact interventions of the last decade are discussed further.

Paediatric ARDS Ashbaugh et al in 1967 first described Adult respiratory distress syndrome (ARDS) primarily in adults. American European consensus conference (AECC) in 1994 renamed ARDS as “Acute respiratory distress syndrome” as this entity was not limited to the adult population.The ARDS accounts for 0.2–2.7% of paediatric ICU admissions. 12% of children admitted for sepsis, viral pneumonia, smoke inhalation, or drowning developed ARDS. Mortality from ARDS in children ranges from 30% to 83%.


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AECC definition focussed on adults and had major shortcomings when applied to children. Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) network along with various intensive care societies across the world organised a Paediatric acute lung injury consensus conference (PALICC).The goals of the conference were 1) To develop a taxonomy to define paediatric ARDS (PARDS), specifically predisposing factors, aetiology, and pathophysiology;2) To offer recommendations regarding therapeutic support of the patient with PARDS; and 3) To identify priorities for future research in PARDS, including defining short-and long-term outcomes5. The new PARDS definition is as shown in Figure 1.

PARDS was graded as per severity irrespective of the age. Oxygenation index (OI) (or Oxygen saturation index (OSI) is used to grade severity of PARDS. P/F ratio was not preferred because of the less standardized approach to positive pressure ventilation in children relative to adults.The requirement of bilateral pulmonary infiltrates in previous definitions was eliminated as the distinction between bilateral and unilateral is often difficult, and there is no evidence that aetiology, treatment, or outcomes are different between patients with and without bilateral infiltrates.Non intubated children were also included to acknowledge the increasing use of noninvasive positive pressure support and to focus on appropriate attention on possible early intervention in PARDS.Children with congenital heart disease and chronic lung disease was also included as chronic disease does not preclude the possibility of superimposed ARDS5.

The PARDS ( Pediatric ARDS) definition

Septic shock Sepsis and septic shock accounts for 6.3% of all PICU admission in the US. Mortality of paediatric sepsis and septic shock has declined since last 50 years.American college of critical care medicine in 2002 published “Clinical parameters for haemodynamic support of Pediatric and neonatal shock” to promote best practices and to improve patient outcomes6. The guideline is as given in Figure 2. This guideline emphasized early use of age-specific therapies to attain time-sensitive goals..Centrers that implemented the guidelines reported better outcomes. Non adherence was associated increased mortality risk6.

Traumatic Brain Injury Motor Vehicle accidents and falls are the major causes for Traumatic brain injury(TBI).The mortality rate from TBI has declined from 22% in 1979 to 11% in 1992. However, survival without serious neurological sequele have not changed for severe brain injury. Secondary neurological insult to TBI is potentially reversible and and if minimised will improve the outcome.Brain trauma foundation guidelines for the acute management of severe traumatic brain injury in infants, children, and adolescents were published in 2003. The immediate management of TBI has been streamlined ever since the introduction of this guidelines.

Paediatric critical care retrieval and transport Critically ill children are transported to alternate facilities for additional care, procedures and interventions which are not available at their current location.

5<051<7.51 7.5<051<12.31 051>12.31

PF ratio<300SF ratio <2641

Figure 1. Pediatric acute respiratory distress syndrome definition. OI=oxygenation index, OSI=oxygen saturation index. Use Pao2-based metric when available. If Pao2 not available, wean F102 to maintain Spo2<97% to calculate OSI or oxygen saturation/F102 ratio. For nonintubated patients treated with supplemental oxygen or nasal modes of noninvasive ventilation, see Figure 3 for at-risk criteria.cAcute respiratory distress syndrome severity groups stratified by OI or OSI should not be applied to children with chronic lung disease who normally receive invasive mechanical ventilation or children with cyanotic congenital heart disease. OI=(F102 x mean airway pressure x 100) /Pao2 OSI=(Fo2x mean airway pressure x 100)/Spo2.

Age Exclude patients with peri-related lung diseaseTiming Within 7 days of known clinical insultOrigin of Edema Respiratory failure not fully explained by cardiac failure or fluid overloadChest Imaging Chest imaging findings of new infiltrate (s) consistent with acute pulmonary parenchymal disease

Oxygenation

Non Invasive mechanical ventilation Invasive mechanical ventilationPARDS (No severity stratification) Mild Moderate Severe

Full face-mask bi-level ventilation orCPAP>5 cm H2O2

4<01<8 8<01<16 01>16

Special Populations

Cyanotic HeartDisease

Standard Criteria above for age, timing, origin of edema and chest imaging with anacute deterioration in oxygenation not explained by underlying cardiac disease. 3

Chronic LungDisease

Standa Criteria above for age, timing, origin of edema with chest imagingconsistent with new infiltrate and acute deterioration in oxygenation from baselinewhich meet oxygenation criteria above.3

Left Ventriculardysfunction

Standard Criteria above for age, timing, origin of edema with chest imaging changesconsistent with new infiltrate and acute deterioration in oxygenation which meetcriteria above notexplained by left ventricular dysfunction.


9

Shock Management Algorithm in Children

They are at increased risk of morbidity and mortality during transport. Meticulous planning and availability of appropriately trained personnel and equipments are vital for ensuring a safe transport. There should not be a dip in quality of care and monitoring during transport. Over the last decade the developed world have successfully implemented specialist retrieval teams. Use of a specialist retrieval team for transfer was associated with improved outcome7. There is high incidence of transport related adverse events during transport in resource limited settings. There is an urgent need to impart paediatric skills to paramedical personnel performing transport in the developing world8.

Paediatric early warning score Cardiopulmonary arrest in children admitted to paediatric wards is not uncommon. This is associated with poor outcome and is many times

preventable. Timely identification and intervention of a deteriorating child has failed at times due to the wide variability of skills and competencies of medical personnel. The wide range of “Normal” values in different paediatric age groups and non specific presentations of various illness adds on to challenges in identifying a deteriorating child. Various children’s hospital across the world attempted to create a simple severity of illness score that could identify sick children early.Early identification would ensure appropriate and timely interventions to prevent cardiopulmonary arrest in children. Paediatric early warning scores ( PEWS) were developed and implemented in various large children’s hospital successfully over last decade9. These scores have been validated and has reduced the ICU mortality and early recognition of children requiring PICU care10.

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0 min

5 min

15 min

60 min

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Recognize decreased mental status and perfusion. Begin high ow O2. Establish IV/10 access.

Initial resuscitation: Push boluses of 20 cc/kg isotonicsaline or colloid up to & over 60 cc/kg until perfusion improve or

unless rales or hepatomegaly develop.Correct hypoglycemia & hypocalcemia. Begin antibiotics.

If 2nd PIV startinotrope.

Monitor CVP in PICU, attain normal MAP-CVP & ScvO2 >70 %

Catecholamine resistant shock: Begin hydrocortisoneif at risk for absolute adrenal insu�ciency.

Cold shock withnormal blood pressure:

1. Titrate uid & epinephrine,ScvO2>70%, Hgb> 10g/dL

2. If SevO2 still <70%Add vasodilator with volumeloading (nitrosovasodilators,

milrininone, imrinone, & others)Consider levosimendan

Warm shock withlow blood pressure:

1. Titrate uid & norepinephrine,ScvO2> 70%,

2. If still hypotensiveconsider vasopressin.

terlipressin or angiotensin3. If ScvO2 still <70%

consider low dose epinephrine

Persistent catecholamine resistant shock: Rule out and correct pericardial e�usion, pneumothorax,& intra-abdominal pressure >12 mm/Hg.

Consider pulmonary, PICCO, or FATD catheter, &/or doppler ultrasound to guideuid, inotrope, vasopressor, vasodilator and hormonal therapies.

Goal C.I > 3.3 & < 6.0 L/min/m2

Cold shock withlow blood pressure:

1. Titrate uid & epinephrine,ScvO2> 70%, Hgb> 10g/dL

2. If still hypotensiveconsider norepinephrine

3. If ScvO2 still <70% considerdobutamine, milrinone.

enoximone or levosimendan

Shock not reversed ?




Fluid refractory shock: Begin inotrope IV/IO.Use atropine/Ketamine IV/IO/IM

to obtain central access & airway if needed.Reverse cold shock by titrating central dopamine

or, if resistant, titrate central epinephrineReverse warm shock by titrating central norepinephrine.

dose range:dopamine up to10 mcg/kg/min.

epinephrine0.05 to 0.3

mcg/kg/min.

Figure 2. Algorithm for time sensitive, goal-directed stepwise management of hemodynamic support in infants and children. Proceed to next step if shock persists.1) First hour goals-Restore and maintain heart rate thresholds, capillary re�ll <2 sec, and normal blood pressure in the �rst hour/emergency department. Support oxygenation and ventilation as appropriate. 2) Subsequent intensive care unit goals- If shock is not reversed, intervene to restore and maintain normal perfusion pressure ( mean arterial pressure [MAP]- central venous pressure [CVP] for age, central venous O2saturation >70%, and CI >3.3, <6.0 L/min/m2 in pediaric intensive care unit (PICU). Hgb, hemoglobin; PICCO, pulse contour cardiac output; FATD, femoral arterial thermodilution; ECMO, extra- corporeal membrane oxygeba-tion; CI cardiac index; CRRT, continuous renal replaement therapy; IV, intravenous; IO, interosseous; IM, intramuscular.

Refractory shock: ECMO


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PEWS chart used at ASTER Medcity Adapted from an original design by the NHS Institute for Innovation and Improvement, England

Conclusion The speciality of Paediatric critical care was born from the need to care for critically ill children. Technological advancements and contributions from specialities like Anaesthesia and Neonatology have contributed immensely to growth of the speciality. Availability of trained Paediatric intensivist and training programme have shown to have improved the care and outcome of children with ARDS,Septic shock , Traumatic brain injury and other diseases11.

Reference1. David Epstein1 and Judith E Brill. A History of Pediatric

Critical Care Medicine. Pediatric Research (2005) 58, 987–996

2. Downes JJ 1992 The historical evolution, current status, and prospective development of pediatric critical care. Crit Care Clin 8:1–22.

3. Dr. S. Ramesh.Paediatric Intensive Care – update. Indian J. Anaesth. 2003; 47 (5) : 338-344.4. Pediatric Intensive care chapter of India . ( http://www.

piccindia.com ).5. Pediatric acute respiratory distress syndrome: consensus

recommendations from the Pediatric Acute Lung Injury

Consensus Conference.Pediatric Acute Lung Injury Consensus Conference Group.Pediatr Crit Care Med. 2015 Jun;16(5):428-39.

6. Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine.Crit Care Med 2009 Vol. 37, No. 2.

7. Ramnarayan P, Thiru K, Parslow RC, Harrison DA, Draper ES, Rowan KM. Effect of specialist retrieval teams on outcomes in children admitted to paediatric intensive care units in England and Wales: a retrospective cohort study. Lancet. 2010 Aug 28;376(9742):698-704.

8. Hatherill M1, Waggie Z, Reynolds L, Argent A. Transport of critically ill children in a resource-limited setting. Intensive Care Med. 2003 Sep;29(9):1547-54

9. The NHS Institute for Innovation and Improvement website www.institute.nhs.uk/PEWScharts

10. Christopher S Parshuram James Hutchison,and Kristen Middaugh. Development and initial validation of the Bedside Paediatric Early Warning System score. Crit Care. 2009; 13(4): R135.

11. Pollack MM, Patel KM, Ruttimann E 1997 Pediatric critical care training programs have a positive effect on pediatric intensive care mortality. Crit Care Med 25:1637–1642.

12. Rogers MC (ed) 2008 Textbook of Pediatric Intensive Care. Williams & Wilkins, Baltimore.


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Metabolic SyndromePurnima K

Aster Wellness, Aster Medcity, KochiAbstract The metabolic syndrome (MetS) is a major and escalating public-health and clinical challenge worldwide in the wake of urbanization, surplus energy intake, increasing obesity, and sedentary life habits. MetS confers a 5-fold increase in the risk of type 2 diabetes mellitus (T2DM), 2-fold the risk of developing cardiovascular disease (CVD) over the next 5 to 10 years [1], 2-to 4-fold increased risk of stroke, a 3- to 4-fold increased risk of myocardial infarction (MI), and 2-fold the risk of dying from such an event compared with those without the syndrome regardless of a previous history of cardiovascular events. Lifestyle modification remains the initial intervention of choice for such population.Keywords: Insulin resistance, abdominal obesity, Lifestyle modification.

Fig.1: Diagnostic criteria proposed for the diagnosis of MetS (2)

Address for communication:Dr. Purnima K, DNB, Dip DiabetologySenior Specialist, Aster Wellness,Aster Medcity, Kochi, KeralaEmail: [email protected]

>100 mg/dL(includesdiabetes)b

>130 mm Hg systolicor > 85 mm Hgdiastolic or on

hypertension Rx

>130/85 mm Hg

TGs >150mg/dL andHDL-C <40mg/dL inmen or <50 mg/dL in

women

TGs >150mg/dLHDL-C <40mg/dL inmen or <50 mg/dL in

women

TGs >150mg/dLand/or HDL-C

<39mg/dL in men orwomen

TGs >150mg/dLand/or HDL-C

<35mg/dL in men or<39 mg/dL in women

BMI > 25 kg/m2

Microalbuminuria:Urinary excretion rate

of >20 mg/min oralbumin: creatinineratio of >30 mg/g.

Other features ofinsulin resistancec

Clinical measures WHO (1998) [5] EGIR (1999) [6] ATPIII (2001)[7] AACE (2003) [8] IDF (2005)[9]

IGT, IFG, T2DM, orlowered insulin

Sensitivity3

plus any 2 of thefollowing

Insulin resistancePlasna insulin >75 th

percentileplus any 2 of the

following

None, but any 3 ofthe following

5 features

IGT or IFGplus any of

the following basedon the clinical

judgement

None

Body weight

Men: waist-to-hipratio >0.90;

women: waist-to-hipratio >0.85 and/or

BMI>30 kg/m2

WC >94 cm in menor >80 cm in women

WC >102 cm in menor >88 cm in women

Increased WC(population speci�c)

plus any 2 of thefollowing

LipidsTGs >150 mg/dL or

on TGs Rx.HDL-C <40mg/dL inmen or <50 mg/dL inwomenor on HDL-C

Rx

Blood pressure >140/90 mm Hg >140/90 mm Hg or onhypertension Rx

>130/85 mm Hg

Glucose IGT, IFG or T2DM IGT or IFG (but notdiabetes)

>110 mg/dL(includesdiabetes)

IGT or IFG (but notdiabetes)

Other

aInsulin sensitivity measured under hyperinsulinemic euglycemic conditions, glucose uptake below lowest quartile for background population under investigation.bIn 2003, the American Diabetes Association (ADA) changed the criteria for IFG tolerance from > 110mg/dl to>100 mg.dl [10].c Includes family history of type 2 diabetes mellitus, polycystic ovary syndrome, sedentary lifestyle, advancing age, and ethnic group susceptible totype 2 diabetes mellitus.BMI: body mass index; HDL-C: high density lipoprotein cholesterol; IFG: impaired fasting glucose; IGT: impaired glucose tolerance; Rs: receivingtreatment;TGs: triglycerides; T2DM: type 2 diabetes mellitus; WC: waist circumference.

Review

Metabolic syndrome (MetS) is defined by a constellation of interconnected physiological, biochemical, clinical, and metabolic factors that directly increases the risk of cardiovascular disease, type 2 diabetes mellitus, and all cause mortality (1).

MetS is considered as a first order risk factor for atherothrombotic complications. There have been several definitions of MetS, but the most commonly used criteria for definition at present are from the World Health Organization (WHO), the European

Group for the study of Insulin Resistance (EGIR) , the National Cholesterol Education Programme Adult Treatment Panel III (NCEP ATP III), American Association of Clinical Endocrinologists (AACE), and the International Diabetes Federation (IDF).


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Country/ethnic group Male (cm ) Female (cm)

EuropidsIn USA, the ATPIII values (102 cm males; 88 cm female) are >94 >80 likely to continue to be used for clinical purposes.South AsiansBaed on a Chines, Malay and Asian-Indian population. >90 >80Chines >90 >80Japanese >90 >80Ethnic South and Central Americans Use South Asians recommendations until more specific data are available.Sub-Saharan Africans Use European data until more specific data are available.Eastern Mediterranean and Middle East (Arabs) population Use European data until more specific data are available.

Waist circumference cut-off

Fig 2 : Gender and age specific waist circumference cut-offs (2)

Fig 3 : Additional criteria as defined by IDF for metabolic syndrome (2)

Epidemiology Worldwide prevalence of MetS ranges from <10% to as much as 84%, depending on the region, urban or rural environment, composition (sex, age, race, and ethnicity) of the population studied, and the definition of the syndrome used. In general, the IDF estimates that one-quarter of the world’s adult population has the MetS (3).

In Indian context, studies show that 1/3rd of the urban population in large cities have MetS; 31.4% have abdominal obesity, 45.6% have hypertriglyceridemia, 65.5% have low HDL, 55.4%

‘Platinum standard’definition-additional metabolicmeasurements for research

Abnormal body fat distribution

General body fat distribution (DEXA)Central fat distribution (CT/MRI)Adipose tissue biomarkers: leptin,adiponectinLiver fat content (MRS)

ApoB (or nin-HDL-c)Small LDL particles

Measurement of endothelial dysfunctionMicroalbuminuria

Elevated high sensitivity C-reactive proteinElevated inflammatory cytokines (eg TNF-alpha, IL-6)Decrease in adiponectin plasma levels

Fibrinolytic factors (PAI-1, etc)Clotting factors (fibrinogen, etc)

Pituitary-adrenal axis

OGTT

Fasting insulin/proinsulin levelsHOMA-IRInsulin resistance by Bergman MinimalModelElevated free fatty acids (fasting and duringOGTT)M value from clamp

Atherogenic dyslipidaemia(beyond elevated trigly ceride and low HDL)

Dysglycaemia

Insuline resis tance(other than elevated fasting glucose)

Vascular dysregulation(beyond elevated blood pressure)

Proinflammatory state

Prothrombotic state

Hormonal factors

Table 3: Additional metabolic measurements for research

The ATPIII definitions were developed which use measurements and laboratory results that are readily available to physicians. However, a major problem with the WHO and NCEP ATP III definitions has been their applicability to the different ethnic groups, especially when trying to define obesity cut-offs. This is particularly evident for the risk of diabetes mellitus, which is apparent at much lower levels of obesity in Asians compared to Europeans. The IDF, having recognized the difficulties has proposed a new set of criteria with ethnic/racial specific cut-offs. There are also some additional criteria as defined by IDF, mainly for research purposes.


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Fig 4: Schematic presentation of MetS (1)(FFA: free fatty acid, ATII: angiotensin II, PAI-1: plasminogen activator inhibitor-1, RAAS: renin angiotensin aldosterone system, SNS: sympathetic nervous system.)

Metabolic syndrome

DyslipidemiaHyperglycemia

overt T2DMHypercoagulable state

Lipoprotein synthesis

Gluconeogeneis

Sodium reabsorption

vasoconstriction

Proinflammatory state

prothrombotic state

Oxidative stress

endothdial dysfunction

Altered release of adipokinesAltered FFA metabolism

Adipose tissue hyperplasia and

hypertrophy

Positive energy balance

Environmental Genetics

� l Thrifty genotype� l Thrifty phenotype

� Physical inactivity� Smoking� Energy dense food� Stress

Factor VIIFactor V

PAI-I

LeptinAT IIAldosterone

Activate RAAS and SNSInsulin resistance

hyperinsulinemiaPortal FFA

Hypertension

Impairs B-cell function

of pancreas

have hypertension, and 26.7% have raised fasting plasma glucose as reported from South India. Rural India has lesser prevalence of MetS at 8-10%.

Prevalence of overweight/obesity in urban children in Delhi has shown an increase from 16% in 2002 and 24% in 2006 to about 29% in 2007. (4)

Pathophysiology MetS is a state of chronic low grade inflammation as a consequence of complex interplay between genetic and environmental factors. Insulin resistance, visceral adiposity, atherogenic dyslipidemia, endothelial dysfunction, genetic susceptibility, elevated blood pressure, hypercoagulable state and chronic stress are the several factors which constitute the syndrome.

a) Abdominal Obesity With obesity and progressive adipocytes enlargement, the blood supply to adipocytes may be reduced with consequent hypoxia. Hypoxia has been proposed to be an inciting etiology of necrosis and macrophage infiltration into adipose tissue that leads to an overproduction of biologically active metabolites known as adipocytokines. Adipocytokines integrate the endocrine, autocrine and paracrine signals to mediate the multiple processes including insulinsensitivity, oxidant stress, energy metabolism, blood coagulation and inflammatory responses which are thought to accelerate atherosclerosis, plaque rupture and atherothrombosis (5). sensitivity, oxidant stress, energy metabolism, blood coagulation and inflammatory responses which are thought to


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endothelin-1 (ET- 1) production, an expression of vascular cell adhesion molecules, and a mitogenic stimulus to vascular smooth muscle cells. In these ways, an insulin resistance leads to the vascular abnormalities that predispose to atherosclerosis.

e) Hypertension Studies suggest that both hyperglycemia and hyperinsulinemia activate the Renin angiotensin system (RAS) by increasing the expression of angiotensinogen, Angiotensin II (AT II), and the AT1 receptor, which, in concert, may contribute to the development of hypertension in patients with insulin resistance. There is also evidence that insulin resistance and hyperinsulinemia lead to SNS activation and, as a result, the kidneys increase sodium reabsorption, the heart increases cardiac output and arteries respond with vasoconstriction resulting in hypertension. It has been recently discovered that adipocytes also produce aldosterone in response to ATII. In this regard, the adipocyte may be considered a miniature renin-angiotensin-aldosterone system.

f) Genetics The thrifty genotype hypothesis proposed by Neel in 1962, individuals living in a harsh environment with an unstable food supply would maximize their probability of survival if they could maximize a storage of surplus energy. Genetic selection would thus favour the energy-conserving genotypes in such environments. However, the selected genetic variations that were favoured during malnutrition would become unfavourable when nutrition improved. Another thrifty phenotype hypothesis was introduced by Hales and Barker in 1992. According to this hypothesis, babies who experienced an intrauterine malnutrition may have adapted to a poor nutrition by reducing energy expenditure and becoming thrifty. These metabolic adaptations are beneficial when individuals are poorly nourished during childhood and adult life; however, with an increased food intake, these adaptations are

Fig 5 : Systemic manifestations of MetS (1)

Renal Microalbuminuria, hypofiltration, hyperfiltration, glomerulomegaly, focal segmental glomerulosclerosis, and chronic kidney disease [99].Hepatic Increased serum transaminase, nonalcoholic steatohepatitis (NASH), non alcoholic fatty liver disease (NAFLD), hepatic fibrosis, and cirrhosis [100].Skin Acanthosis nigricans, lichen planus, systemic lupus erythematosus, burn-induced insulin resistance, psoriasis, androgenetic alopecia, skin tags, skin cancer, and acne inversa [101].Ocular Nondiabetic retiocclusion, age related cataract-nuclear, cortical, posterior subcapsular; central retinal artery occlusion, primary open angle glaucoma, oculomotor nerve palsy, and lower lid entropion [102]Sleep Obstructive sleep apnea (OSA)[103].Reproductive system Hypogonadism, polycystic ovarian syndrome (PCOS), and erectile dysfunction [104].Cardiovascular system Coronary heart disease (CHD), myocardial infarction (MI), and stroke [105].Cancers Breast, pancreas, and prostrate [106].

Table 3: Systemic effects of Mets.

accelerate atherosclerosis, plaque rupture and atherothrombosis (5).

b) Free fatty acids (FFA) Upper body subcutaneous adipocytes generate a majority of circulating FFA while an intra-abdominal fat content has been positively correlated with the splanchnic FFA levels which may contribute to the liver fat accumulation commonly found in abdominal obesity. a chronic exposure of the pancreas to the elevated FFA impairs a pancreaticβ-cell function. FFAs increase fibrinogen and PAI-1 production.

c) TNF alpha It is a paracrine mediator in adipocytes and appears to act locally to reduce the insulin sensitivity of adipocytes. Evidence suggests that TNF-α induces adipocytes apoptosis and promotes insulin resistance by the inhibition of the insulin receptor substrate 1 signalling pathway.

d) Insulin Resistance 6

It is defined as a pathophysiological condition in which a normal insulin concentration does not adequately produce a normal insulin response in the peripheral target tissues. This accentuation of some insulin actions coupled with a resistance to other actions of insulin results in the clinical manifestations of MetS. Binding of insulin results in a tyrosine phosphorylation of downstream substrates and activation of two parallel pathways: the phosphoinositide 3-kinase (PI3K) pathway and the mitogen activated protein (MAP) kinase pathway. The PI3K-Akt pathway is affected, while, the MAP kinase pathway functions normally in insulin resistance. Inhibition of the PI3K-Akt pathway leads to a reduction in endothelial NO production, resulting in an endothelial dysfunction, and a reduction in GLUT4 translocation, leading to a decreased skeletal muscle and fat glucose uptake. By contrast, the MAP kinase pathway is unaffected, so there is a continued


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no longer beneficial and would lead to an increased risk of MetS in a later life (7).

Treatment: Effective preventive approaches include lifestyle changes, primarily weight loss, diet and exercise, and the treatment comprises the appropriate use of pharmacological agents to reduce the specific risk factors. Pharmacological treatment should be considered for those whose risk factors are not adequately reduced with the preventive measures and lifestyle changes. For the treatment of risk factors of MetS, the physician should follow the current treatment guidelines of the National Cholesterol Education Programme (NCEP), the seventh Joint National Com-mission (JNC-VIII) for blood pressure treatment, the American Diabetes Association (ADA), the American Heart Association (AHA), and the National Institute of Health Obesity Initiative.

a) Weight Reduction Four therapies can be used for weight reduction: calorie restriction (e.g., 500 kcal/d deficit), increased physical activity, behavioural modification, and, in appropriate patients, FDA-approved weight-reducing drugs. Several authors recommend a weight loss goal of 10% reduction in body weight in the first six months to a year and continued weight loss thereafter until BMI is less than 25. Both the Finnish Diabetes Prevention Study and the US Diabetes Prevention Program (DPP) showed that diet and exercise had a significant effect on reducing the progression from IGT to T2DM.

b) Diet The effective and healthful methods for the long-term weight loss are reduced-energy diets, consisting of a modest 500 to 1000 calories/day reduction. The DASH diet plan and a Mediterranean diet are highly recommended (high in fruits and vegetables and low in saturated fats and dairy products) (8). ATP III recommended that the diet should contain 25% to 35% of calories as total fat for the individuals entering cholesterol management. If the fat content exceeds 35%, it is difficult to sustain the low intakes of saturated fat required to maintain a low LDL-C. On the other hand, if the fat content falls below 25%, TGs can rise and decline in HDL-C levels can be seen; thus, a very low-fat diet may exacerbate an atherogenic dyslipidemia. A protein intake of 10–35% of total calorie intake is recommended by the Institute Of Medicine (IOM) for the general population with an exception of individuals with chronic kidney disease (CKD) who have markedly reduced glomerular filtration rate, where, an excess protein enhances phosphorus load, which can cause acidosis and worsen the insulin resistance. A sodium

restriction has also been associated with reduced CVD events and congestive heart failure. Guidelines therefore recommend that a daily sodium intake should be restricted to no more than 65–100 mmol and recommend the intake of foods enriched with potassium, such as fruits and vegetables, with a goal of 90–120 mmol of potassium per day. Incorporation of monounsaturated fatty acid (fat from plant source like olive oil, soybean oil, canola oil, safflower oil, peanut oil, peanuts, peanut butter, almond, and cashew nut) may be beneficial as it improves the atherogenic dyslipidemia. Similarly, n-3 polyunsaturated fatty acids (mainly from fish) have cardioprotective effect and it should constitute approximately 10% of total energy intake. Viscous (soluble) fibres (mainly in oat products, psyllium, and pectin) intake of 10– 25 g/day also improves an atherogenic dyslipidemia. Low glycemic index foods (i.e., those that are minimally processed) have been shown to improve the components of the MetS. Therefore, a diet high in complex, unrefined carbohydrates with an emphasis on fibres (10-25g/1000 calories consumed daily) and low in added sugars (≤25% of calorie intake) is recommended for individuals with or at risk of the MetS.

c) Physical Activity Current physical activity guidelines recommend practical, regular, and moderate regimens for exercise. The standard exercise recommendation is a daily minimum of 30 minutes of moderate-intensity physical activity. Current AHA guidelines call for a clinical assessment of the risk of the future ASCVD events before initiating a new exercise regimen. For high-risk patients (e.g., those with recent acute coronary syndromes or recent revascularization), physical activity should be carried out under the medical supervision. Clinicians should evaluate which type of activity is feasible for the patient, considering the barriers (e.g., arthritis and time constraints) that can prevent a successful increase in the physical activity. Accordingly, they should assist patients in developing a physical activity plan based on the initial assessment. However, any type of physical activity should be encouraged. Lifestyle activity should be increased slowly in intensity and duration (by 5 min/session/week), starting from a low-intensity exercise (<3 metabolic equivalent) in sedentary subjects, to avoid excessive fatigue, muscle pain, strains, or injuries (9).

d) Pharmacological Therapy The National Institutes of Health guidelines for the treatment of obesity recommend a consideration of pharmaceutical therapy for weight loss for the individuals with a BMI of at least 30 kg/m2 or for those with a BMI of at least 27 kg/m2 and comorbidities associated with their excess weight. Pharmacological


16

Fig 6: JNC VIII guidelines for hypertension management (11)

Implement lifestyle interventions(continue throughout management).

General population(no diabetes or CKD) Diabetes or CKD present

Set blood presssure goal and initiate blood pressure lowering-medicationbased on age, diabetes, and chronic kidney disease (CKD).

Adult aged 18 years with hypertension

Age < 60 years All agesDiabetes presentNo CKD

All agesCKD present withor without diabetes

Blood pressure goalSBP <140 mm HgDBP < 90 mm Hg

Initiate ACEI or ARB, aloneor in combination with otherdrug class.

Initiate thiazide-type diureticor CCB, aloneor in combination.

Initiate thiazide-type diureticor ACEI or ARB or CCB, aloneor in combination.



Nonblack Black All races


Age > 60 years

approaches to weight loss include two main classes: appetite suppressants and inhibitors of nutrient absorption. A single agent is generally recommended and an average weight loss ranges greatly from 5% to 10% of initial weight. Appetite suppressants include phentermine derivatives and sibutramine. These agents are usually taken in the late morning and reduce appetite in the late afternoon and evening. Orlistat (an inhibitor of gastrointestinal lipase) is the only nutrient absorption inhibitor currently available. It prevents absorption of up to 30% of the fat consumed and must be taken at the time of consumption. Undesirable side effects such as flatulence and oil leakage in the stool often occur early in the course of treatment with this medication. In randomized clinical trials, orlistat in obese persons with T2DM at baseline led to an improved glycemic control and a weight reduction of 6% over 1 year versus 4% weight loss with placebo.

e) Bariatric Surgery Surgery is recommended for the individuals who do not respond to weight loss diet or medications, are extremely obese (BMI > 40 kg/m2 ), or if they have a BMI > 35 to 40 kg/m2 and one or more comorbid conditions. Bariatric surgery techniques using laparoscopic adjustable banding of stomach along with Roux-en-Y and other forms of gastric bypass are now favoured for the severe and morbid obesity. It results in a weight loss of 25–30% and rapid normalization of glucose handling and blood pressure in patients with diabetes and hypertension

with 95% of patients being free of the syndrome one year after a surgery. It has been found to be associated with the improvement and resolution of multiple comorbidities associated with obesity.

f) Dyslipidemia (10) The AHA/ACC 2013 guidelines on statin therapy recommends statin in the following cases:

1) Individuals with clinical ASCVD

2) Individuals with LDL >190

3) Individuals with diabetes, 40-75 years old with LDL 70-189 and without clinical ASCVD

4) Individuals without clinical ASCVD or diabetes with LDL 70-189 and estimated 10-year ASCVD risk >7.5%

The guidelines recommend that the LDL-C goals should be set at less than 130 mg/dL with the option of targeting less than 100 mg/dL in the moderately high-risk individuals. Target goals should be set at an LDL-C less than 100 mg/dL in the high-risk patients with the option of aiming for less than 70 mg/dL in the “very high-risk”patient .If the TGs level is higher than 500 mg per dL, then lowering the TGs level to 500 mg per dL or less takes primacy over LDL-C lowering to prevent the development of acute pancreatitis. After LDL-C and non-HDL-C goals are achieved, a tertiary target is raising the HDL-C level.


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Statins are considered to be the most effective class of drugs for reducing the LDL-C concentrations due to their minimal drug-drug interactions and side effects. Non-lipid-lowering or pleiotropic effects of statins have also been implicated in their beneficial effects on inflammation, endothelial function, and CVD events and may therefore be beneficial for individuals with the MetS. Niacin has favourable effects on essentially all of the abnormalities of the metabolic dyslipidemia. The two fibrates currently used clinically are gemfibrozil and fenofibrate, both of which can lower TGs by 25% to 30% with the greater reductions in individuals that are hypertriglyceridemic. The advantage of gemfibrozil is that it is lower in cost, but fenofibrate has a fewer drug interactions, especially when prescribed along with a statin.

g) Hypertension (11) Hypertension leads to myocardial infarction, stroke, renal failure, and death if not detected early and treated appropriately. As per JNC VIII guidelines, any hypertension with BP more than 140/ 90 mm Hg should be treated with lifestyle interventions and if needed medications.

h) Insulin Resistance and Hyperglycemia In MetS, patients with IFG (or IGT if assessed), weight reduction, increased physical activity, or both will delay (or prevent) the onset of T2DM. In addition, metformin, thiazolidinediones , and acarbose will lower the risk of T2DM in people with IFG or IGT. Metformin, which has a primary mechanism of action of reducing hepatic glucose production, has been shown to reduce the progression of diabetes from IGT.

Conclusion Lifestyle modification remains the initial intervention of choice for such population. Modern lifestyle modification therapy combines specific recommendations on diet and exercise with behavioral strategies. Pharmacological treatment should be considered for those whose risk factors are not adequately reduced with lifestyle changes. This review provides summary of literature related to the syndrome’s definition, epidemiology, underlying pathogenesis, and treatment approaches of each of the risk factors comprising.

References1. Jaspinder Kaur. A comprehensive review on Metabolic

syndrome. Cardiology Research and Practice. Volume 24, Article ID 943162, 21 pages.

2. International Diabetes Federation: The IDF consensus worldwide definition of the metabolic syndrome, http://www.idf.org/metabolic-syndrome.

3. A. J. Cameron, J. E. Shaw, and P. Z. Zimmet, “The metabolic syndrome: prevalence in worldwide populations,”

Endocrinology and Metabolism Clinics of North America, vol. 33, no. 2,

pp.351–375, 2004.4. Pandit K, Goswami S, Ghosh S, Mukhopadhyay P,

Chowdhury S. Metabolic syndrome in South Asians. Indian J Endocr Metab 2012;16:44-55.

5. A. M. Xydakis, C. C. Case, P. H. Jones et al., “Adiponectin, inflammation, and the expression of the metabolic syndrome in obese individuals: the impact of rapid weight lose through caloric restriction,” Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 6, pp. 2697–2703, 2004.

6. D. G. Carey, A. B. Jenkins, L. V. Campbell, J. Freund, and D. J. Chisholm “Abdominal fat and insulin resistance in normal and overweight women: direct measurements reveal a strong relationship in subjects at both low and high risk of NIDDM,” Diabetes, vol. 45, no. 5, pp. 633–638, 1996

7. C.N.Hales andD. J. P. Barker, “Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis,” Diabetologia, vol. 35, no. 7, pp. 595–601, 1992.

8. N. Babio, M. Bull´o, J. Basora et al., “Adherence to the Mediterranean diet and risk of metabolic syndrome and its components,” Nutrition, Metabolism and Cardiovascular Diseases, vol. 19, no. 8, pp. 563–570, 2009.

9. W. L. Haskell, I.-M. Lee, R. R. Pate et al., “Physical activity and public health: updated recommendation for adults from the American College of Sports Medicine and the American Heart Association,” Circulation, vol. 116, no. 9, pp. 1081–1093, 2007.

10. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PWF. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(suppl 2):S1–S45.

11. Paul A. James, MD; Suzanne Oparil, MD; Barry L. Carter, PharmD; William C. Cushman, MD; Cheryl Dennison-Himmelfarb, RN, ANP, PhD; Joel Handler, MD. 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults. Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-520. doi:10.1001/jama.2013.284427.


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Under addressed neurocognitive issues in neurological disorders

Sandhya CherkilNeuropsychologist, Aster Medcity, Kochi

Introduction Brain being a complex structure with innumerable neural connections, tracts and their interplay with neurotransmitter mechanisms, there is still no complete understanding of its nature, its complexity, and mechanisms involved in cognition and behavior1. When there is a structural change in the previously normal functioning brain like a tumor, aneurysm, or a bleed, it is only logical to assume that there is going to be a functional change as well. However, in our country, this aspect is poorly understood and in many an instance not addressed at all. This issue rarely features in the treatment or follow up plans. Though there are a few centers which looks at this neurocognitive issue in neurological disorders as per the demands and requests from the patients or their relatives, and despite being focused in the pure research as well as in clinical trials, it is not part of the treatment/management protocol.

Cognition and its implications Implications of cognition in one’s existence is multi-faceted. It has connotations deeper than memory and attention, though usually it is by these terms the concept of cognition is widely understood. Cognition has different aspects to it, the basic ones being attention, memory and information processing2. Without intact cognition, the assimilation of, interaction with, and interpretation of the experience with outer as well one’s inner world suffers. With its basic cognitive functions of attention,

memory, and information processing intact, brain can then effectively employ the learning centers of the brain and thus benefit from interactions, exposure and experience. Further these basic functions aid the brain in executive functions – which constitutes the decision making capability, judgment, error detection and correction, and mental flexibility or set shift3. Set shift in simpler words is the ability of the brain to make a response which is not customary, after engaging in a series of repetitive and habitual responses. All the cognitive functions together results in learning.

Another often less known function of the cognition, but with great social and personal implication is the aspect called social cognition. Social cognition helps an individual to maintain the decorum of the social behavior across different situations, events and people. It helps in the learning that happens in social situations; aids in empathy; and supports the individual to exercise control over one’s impulses and strong emotions and modify and express them in a socially acceptable way4. Social cognition determines perceptions of aggression, altruism, obedience, morality and love.

Abstract With the advent of information explosion and increased media access, awareness about health and its many faceted concerns gained momentum. As a result, today public is more aware of different health conditions, treatments, and outcomes of different disease conditions including neurological ones. Compared with the knowledge of a few decades back, today’s public is no stranger to words like tumor, stroke and aneurysm. In the event of a relative or a friend being diagnosed with any of these neurological disorders, people do have an idea as to what specialist should be consulted and what would be the regimen of the treatment be like. Their expectations do not fall short as many of them witness the battle against the disease, hear the reassurances that all is well and see their dear ones ready to return to their former lives. But later, in a few months’ time, they start to sense that something is amiss. In some instances there are problems with memory which reduces their functionality at home and work, in others there is an inability to function under stress, or a tendency to fall apart when multiple demands are made on them, relatives and friends of yet others become distressed when they sense that the person they had known before has been changed subtly, and yet another set of people manifests symptoms of anxiety and depression, and psychosis in rare instances. This article tries to give an over view of cognition, its implications and the need for assessment and remediation in neurological disorders.

Address for correspondence:Sandhya Cherkil, Neuropsychologist,Department of Neurosciences,Aster Medcity, KochiEmail: [email protected]

Memory andLearning

LEARNING

ExecutiveFunctioning

AttentionLanguage

SocialPerception

VisuospatialProcessing

SensorimotorFunctioning

LEARNING - A MULTIFACTORIAL PROCESS

Review


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Figure 2. Determinants of social cognition: under personal determinantscomes the cognitive factors

With a brain that is impaired in cognition, it is to be expected that the former patients of neurological disorders will exhibit difficulties in their memory and attention. In a majority of the patients, this is seen to be the most common complaint. On detailed assessment very often deficits in other cognitive domains too come out like difficulties with visuo spatial perception and functioning and linguistic abilities. While difficulties with visuo spatial functioning are manifested as problems of navigation in the person’s living space and geography, linguistic disabilities parade as word finding difficulties, comprehension of written and spoken language, and an inability express themselves verbally or using written language.

However there are also instances where the prominent difficulties are in the area of personality change5, where a premorbidly outgoing and social person ceases to be so; where a person becomes, miserly and guarded where money is concerned; where a previously meticulous and fastidious person becomes slovenly and disorganized. More serious are the instances where the patient exhibits anxiety disorders6 like panic disorder, post-traumatic stress disorder, generalized anxiety disorders and obsessive compulsive disorder. Some patients show symptoms of psychosis. So the larger picture that emerges is suggestive of not just impairments in memory and/or attention, but gross dysfunctions that are bound to have an impact on the quality of life7 of the patient as well as his/her caregiver.

So what has quality of life got to do with cognition? Knowingly, or unknowingly this is what we all strive to achieve. Quality of life becomes very important particularly in the cases where there is no real hope, because that is all one can ensure the patient to have. One important aspect of an intact cognition is the awareness of the reality as it truly is, and this gives a sense of being in control of things. With an impaired cognition the person is left with a half –understanding of things happening around him/her, which makes the patient dependent on others to clarify his/her version of reality, as well as to make sense out of the chaos of his inner world. This takes a toll on the quality of life of both the patient

as well as the relative. Impaired or intact cognition is a determinant of occupational functionality, social functionality, interpersonal relationships, treatment decisions, and informed consent8.

Assessment of cognition and remediation So the next pertinent question will be what could be done to improve cognition in patients with neurological disorders? The first step will be to assess the cognitive status of the patient, so that the cognitive strengths and limitations of the patient is understood9. This knowledge is important to the therapist, so that remedial programs tailor made for each patient could be chalked out depending on his/her strengths and weaknesses. While in some instances remedial programs are restorative

PersonalDeterminants

EnvironmentalDeterminants

BehavioralDeterminants


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Figure 3 Example of visuospatial deficits in a stroke patient, where the patient drawing showed significant disparity between the original stimulus in the left and its copy

in nature, in others it is compensatory10. Either way, it reduces the dependency of the patient on the relatives and empowers him/her with a sense of control and predictability. Tangible results will be in the areas of occupational and academic functionality. The patient along with the remedial programs also should receive consistent psychological support, once again approaches tailor made according to the requirement. Caregivers are also met time to time to gauge the progress, detect any new difficulties and to give them necessary support through therapy if it is called for and psycho education.

ConclusionThere are clinical evidences as well as backing from the research and clinical trials that the patients do benefit from cognitive interventions and psychotherapy, which improves quality of life and functionality. There needs to be focus on the cognitive, behavioral and psychological needs and problems of this patient group once the patient is stabilized medically, which in the current scenario is largely overlooked.

References1. Gazzaniga MS. Neuroscience and the correct level of

explanation for understanding mind. Trends Cogn Sci. 2010;14:291–292

2. Deutsch JA., Deutsch D. Attention: Some Theoretical Considerations. Psychological Review, 1963;70: 80–90.

3. Elliot R. Executive functions and their disorders: Imaging in clinical neuroscience. Br Med Bull, 2003; 65: 49-59.

4. Huitt, W. Social cognition. Educational Psychology Interactive. Valdosta, GA: Valdosta State University. 2006;

Retrieved [20/02/2015], from http://www.edpsycinteractive.org/topics/soccog/soccog.html

5. Koponen, S., Taiminen, T., Portin, R., Himanen, L., Isoniemi, H., Heinonen, H., ... Tenovuo, O. Axis I and II psychiatric disorders after traumatic brain injury: A 30–year follow–up study. Am J of Psych, 2002;159: 1315–1321.

6. Wise MG, Rundell JR. Anxiety and neurological disorders.SeminClin Neuropsychiatry, 1999; 4:98-102.

7. Taphoorn, M. J. B., Klein, M. (2004). Cognitive deficits in adult patients with brain tumor. The Lancet Neurology, 3,159-168

8. Liu R, Page M, Solheim K, Fox S, & Chang SM.(2009). Quality of life in adults with brain tumors: Current knowledge and future directions. Neuro Oncology, 2009; 11: 330-339.

9. FoxSW, MitchellSA, Booth-Jones M. Cognitive impairment in patients with brain tumors: assessment and intervention in the clinic setting. ClinJ OncoNurs, 2006; 10: 169-176.

10. Samuel R. Cognitive rehabilitation for reversible and progressive brain injury. IndJ Psychiatry, 2008;50:282-284.


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Introduction Among the vascular causes of hematuria, renal arteriovenous malformations are very rare. The term, though used as a blanket term for any abnormal arteriovenous communication, traditionally refers specifically to abnormal communication between a renal artery or its branches and the renal vein or its tributaries with an intervening nidus; and the direct arteriovenous communication that is usually acquired is called arteriovenous fistula.1,2They present most

n-butyl 2 Cyanoacrylate Embolization ofCongenital Renal Arteriovenous Malformation

Krishna Prasad BP, Vijay Jayakrishnan,Kishore T A, Narayanan Unni,

Department of Clinical Imaging and Interventional Radiology,Department of Nephrology and Urology, Aster Medcity, Kochi

Case Report

Abstract The term renal arteriovenous malformation is traditionally used for congenital arteriovenous communication with an intervening nidus. These are further classified into angiomatous and cirsoid forms. They present with hematuria, hypertension, renal dysfunction or rarely circulatory failure. Therapy has advanced from open surgery (often necessitating nephrectomy) to minimally invasive endovascular embolization. Embolization materials traditionally used include pushable coils, alcohol, particles (gel foam, polyvinyl alcohol), glue (n-butyl 2 Cyanoacrylate) and vascular plug depending on the type of communication, number of feeders, speed of flow and material availability.Keywords: Hematuria, cirsoid, arteriovenous malformation, embolization, n-butyl 2 Cyanoacrylate.

Figure 1. Ultrasound Doppler showing cluster of flow signal with aliasing in the right renal hilum (white arrow) with no discernable parenchymal flow signal (in this particular flow setting) and mildly increased renal cortical echotexture.

commonly with hematuria and backpain, with other clinical manifestations being clot colic, hypertension, renal dysfunction, circulatory failure,and left ventricular hypertrophy.3-6We present a case of cirsoid right renal AVM who presented with recurrent hematuria and right sided back pain and describe its spectrum of diagnostic appearance, successful minimally invasive endovascular treatment with three one month follow-up.

Address for communication:Dr. Vijay Jayakrishnan, Lead Consultant,Neuro Radiology, Aster Medcity, KochiEmail: [email protected]

Case Report A 51 year old gentleman from Kerala presented with recurrent episodes of mild hematuria and right sided back pain (once every two to four months) since past twenty years which had increased in frequencyand accompanied by clot colic since past one


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Figure 2. CT renal angiography in late arterial phase showing right renal hypoperfusion, tangle of blood vessels in the hilum (*), enlarged interpolar segmental artery(white arrowhead) andearly opacification of right renal vein (white arrows). The left kidney is normal.

Figure 3. Digital subtraction angiography with right renal artery (left) and selective interlobar segmental artery (right) injections confirming a cirsoid arteriovenous malformation with nidus supplied by multiple feeders (black arrowheads) from the interlobar segmental artery and early draining renal vein (black arrows).

year (once or twice every month). Plain radiograph and unenhanced CT performed elsewhere had showed no calculus and the patient had been managed conservatively. His blood pressure was 160/96 and he was on Telmisartan 20 mg once a day.

Imaging findings: Ultrasound with Doppler showed cluster of flow signal with aliasing in the right renal hilum

with minimal discernable parenchymal flow signal (Figure 1). The cortex was mildly echogenic (Grade 1 renal parenchymal disease) with preserved corticomedullary differentiation and normal renal dimension (9.7 cm length). CT renal angiography in late arterial phase showed decreased opacification of the right kidney, tangle of blood vessels in the medial aspect of


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Figure 4. Post embolization floro showing glue cast filling the nidus.

Figure 5. Digital subtraction post procedure angiography with right renal artery (left) and selective interlobar segmental artery (right) injections showing complete exclusion of the arteriovenous malformation from the circulation, occlusion of an interlobar vessel and normal flow through the rest of the vessels.


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Figure 6. Post embolization day 1 Ultrasound Doppler performed using the same Doppler settings as the pre embolization Doppler study showing no abnormal hilar flow signal and good Doppler signal in intralobar (white arrowheads) and arcuate vessels (white arrows).

interpolar region, enlarged interpolar segmental artery, abnormal opacification of right renal vein and normal left kidney (Figure 2).Conventional angiography through right brachial access with right renal, selective intralobar and a superselective feeder artery injections confirmed the diagnosis, with nidus measuring 4.7 x 3 cm, fed by multiple feeders from two branches of an interpolar segmental artery (Figure 3).

Endovascular management Using standard cathlab operative protocol, right femoral access was obtained and a 6 French sheath was introduced (Cook Medical, Bloomington, USA). A 6 French Renal Double Curve guiding catheter (Cook Medical, Bloomington, USA) was positioned within the right renal artery;a 5 French Vertebral artery catheter (Cook Medical, Bloomington, USA) was used to cannulate the interlobar artery and Progreat microcatheters (Terumo Medical Corporation, Somerset) were coaxially introduced to intubate successively two major culprit feeders and the nidus was embolized with a liquid embolization mixture of n-butyl 2 Cyanoacrylate (Histoacryl blue, B Braun,Melsungen AG) diluted with lipoidol (Guerbet, Bloomington, USA) in the ratio of 1:2. Post embolization floro showed glue cast filling the nidus

and an interlobar artery (Figure 4) and angiography showed complete exclusion of arteriovenous malformation and an interlobar vessel, normal flow through the rest of the renal arteries and absent opacification of renal vein in arterial phase (Figure 5). Hemostasis was secured by manual compression. Procedure was uneventful.

Day 1 post procedure plain CT of the lung showed four very small foci of pulmonary glue emboli, the patient however developed no respiratory issues. Right renal Doppler showed good parenchymal flow and absent flow in nidus (Figure 6). Patient was discharged.

Discussion Abnormal arteriovenous communications in the kidney can be classified as angiomatous, aneurysmal and cirsoid.1-3,5Aneurysmal variety is acquired and is due to trauma, usually iatrogenic (post biopsy or percutaneous nephrostomy) and is due to aneurysmal rupture into a renal vein or its tributary. The congenital variety characterized by a nidus between arterial and venous components accounts for 20 % of arteriovenous communications and is of two types, the angiomatous and cirsoid variants. Angiomatous variant is smaller with single


25

feeding vessel and the cirsoid variety is larger with multiple arterial feeders.6,7They are unilateral, however a case of bilateral AVM has been reported.8

Most common clinical presentation is recurrent hematuria with back pain, the other clinical manifestations being clot colic, hypertension, renal dysfunction, circulatory failure, and left ventricular hypertrophy.3-6,8Hematuria is due to rupture of thin walled small veins into calyces secondary to venous hypertension, which is why the chance and severity of bleed does not depend on the size of the nidus but depends on the amount of shunting.8Systemic hypertension is seen in 50 % of patients with AVM.8

Since they present with hematuria, diagnostic path is usually to exclude calculus and tumor5, including ultrasonography and CT which most of the time raises the suspicion of vascular abnormality and sometimes characterizes feeder vessels if contrast enhanced angiographic phase is obtained in CT. MRI if performed shows multiple punctate and serpiginous T2 hypointensities representing flow voids.1,3,4,8Crowded vessels in the hilum might lead to diagnostic difficulties in cross sectional imaging.5Conventional angiography is the gold standard investigation and has to performed with a high frame rate to characterize high flow.1,3,4 Angiography typically shows rapid passage of contrast from the artery into the vein through a nidus or an area of faint blush. Feeding vessel characteristics including number, origin, size and, flow velocity can be determined.

Small arteriovenous malformations (< 1.5 cm) which are asymptomatic can be managed conservatively.4,8 Larger lesions (> 2.5 cm) and those which are symptomatic irrespective of size need to be treated.4,8Therapy has advanced from open surgery (often necessitating nephrectomy) to minimally invasive endovascular embolization.1-11The advantages of endovascular treatment include avoidance of any form of nephrectomy, low hospital morbidity, lesser duration of stay, and decreased incidence of renal ischemia.6,8 Embolization materials traditionally used include pushable coils, alcohol, particles (gel foam, polyvinyl alcohol), glue and vascular plug depending on the type of communication, number of feeders, speed of flow and material availability.1,9 Liquid agents are preferred in cirsoid malformation since they achieve embolization of nidus along with the feeding vessels, and usage of liquid agents alone or with coils have showed a better result than when coils were used in isolation.9-11

Complications of endovascular treatment include post embolization syndrome, which is less common due to subselective cannulation of the arterial feeders; inadvertent embolization due to reflux of glue and catheter getting adhered to glue cast (which might require surgery).12

Conclusion Endovascular management of renal arteriovenous malformation with liquid agents like glue (n-butyl 2 Cyanoacrylate) is efficacious and are preferred over particles or coils since they achieve penetration into the nidus achieving complete embolization and decreased chance of recurrence in most treated cases.

References1. Chimpiri AR, Natarajan B. Renal vascular lesions: diagnosis

and endovascular management. Semin Intervent Radiol. 2009;26(3):253-61.

2. Sunil Kumar, Yashwant Lonkar, Amar Amale, Diwan S K, Pankaj Banode. Gross hematuria due to renal arteriovenous malformation successfully treated with embolization in an elderly patient. J Clin Gerontol Geriatr. June 2013. Volume 4, Issue 2, Pages 62-64.

3. Thayaparan A, Amer T, Mahdi E, Aboumarzouk O, Hughes O. Complete renal artery embolization in a comorbid patient with an arteriovenous malformation. Case Rep Urol. 2014;2014:856059.

4. Wiesinger B, Schöber W, Tepe G, Erley C, Duda SH. Complication after embolization of a complex renal vascular malformation. Nephrol Dial Transplant. 2005;20(8):1729-33.

5. Defreyne L, Govaere F, Vanlangenhove P, Derie A, Kunnen M. Cirsoid renal arteriovenous malformation treated by endovascular embolization with n-butyl 2-cyanoacrylate. Eur Radiol. 2000;10(5):772-5.

6. Carrafiello G, Laganà D, Peroni G, et al. Gross hematuria caused by a congenital intrarenal arteriovenous malformation: a case report. J Med Case Rep. 2011;5:510.

7. Poh PG, Tan BS, Tham SC, et al. The use of n-butyl-2 cyanoacrylate as an embolic agent in the minimally invasive treatment of renal arteriovenous malformations. Ann Acad Med Singap. 2013;42(4):207-9.

8. Radhiana H, Mohd Shafie A, Mohd Ariff MA. Bilateral congenital renal arteriovenous malformation: A rare entity with uncommon presentation. Int Med J. June 2009. Volume 8 Number 1.

9. Takeuchi N, Nomura Y. Ruptured renal arteriovenous malformation successfully treated by catheter embolization: a case report. BMC Res Notes. 2014;7:19.

10. Yasui D, Murata S, Onozawa S, et al. Endovascular treatment for renal arteriovenous malformations using liquid embolization agents. J Vasc Interv Radiol. 2014 March, Volume 25, Issue 3, Page S203.

11. Murata S, Onozawa S, Nakazawa K, et al. Endovascular embolization strategy for renal arteriovenous malformations. Acta Radiol. 2014;55(1):71-7.

12. Sharma V, Kumar S, Singh S, Mandal A. Glued angiocatheter: a rare complication of intrarenal pseudoaneurysm glue angioembolization. Korean J Urol. 2014;55(6):426-9.


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Abstract Gastrointestinal stromal tumor (GIST) is a rare non epithelial tumor of GI tract and commonest site being stomach. Small bowel GISTs are rare, most often detected accidentally and surgery is mainstay of treatment. Even though laparoscopic resection is an accepted procedure for GISTs, it’s rarely reported as a procedure for large jejunal GISTs. We report a case of a large jejunal GIST successfully resected by advanced minimal access techniques and the relevant literature is reviewed.

Laparoscopic Resection of Large Jejunal GIST

Iyoob V A, Shailesh C, Nanda KGastroenterology & Hepatology, Pathology, Aster Medcity, Kochi

Case history 65 year-old-man was presented to the OPD with complaints of mass lesion in the lower abdomen noticed by himself. He did not have any bowel related symptoms/GI bleed. No abdominal pain/loss of appetite or weight. He was diabetic on oral hypoglycemic drugs with poor glycemic control and on drugs for BPH. Clinical examination showed a slightly tender hard mass with limited mobility in the left iliac fossa. PR examination was normal apart from enlarged prostate. Contrast enhanced CT of abdomen showed a 11.7X10X10 cm lobulated mass with heterogeneous post contrast enhancement displacing small bowel and colon (Fig 1a, b). Mild left sided hydronephrosis and enlarged prostate were also present. In view of suspected GIST and lesion was operable we proceeded with Laparoscopy. Intra-operative finding was large lobulated fleshy tumor arising from 15cm from duodeno-jejunal flexure with a stalk like attachment to the bowel wall. The mass was adherent to the parietal peritoneum at the region of left inguinal region compressing left ureter, gonadal vessels and vas. There were no evidence of liver metastasis, LNs or ascites (Fig 1c). Tumor was detached from the jejunum with firing of 60mm Endo GIA (Covedian) and en-mass resection of parietal peritoneum with clear margins done separating it from the gonadal vessels and ureter. Tumor was placed in uro-bag and morselated after taking the margins of resection for histopathology. Umbilical port site was extended for 5cm for removal of specimen (Fig 1d) Post-operative period was uneventful and patient was discharged on 4rd post-operative day. Histopathology of specimen showed interlacing fascicles of spindle cells with necrosis, and moderately pleomorphic nuclei in HPF (Fig

Fig 1. Areterial (1a) and venous (1b) phase of CT scan abdomen. Intraoperative picture of tumor(1c) and post-operative picture \ showing the port sites and small incision at umbilicus (1d)

Fig 2. Interlacing fascicles of spindle cells with necrosis (2A), moderately pleomorphic nuclei in HPF (2B). Immuno histochemistry showing strong immunoreactivity for CD117 (2C), Ki-67 proliferation index of 8% (2D)

Address for correspondence:Dr. V A Iyoob MS, MCh, FRCSLead Consultant, GI, Minimal Access and Robotic Surgery,Gastroenterology & Hepatology, Aster Medcity, KochiEmail: [email protected]

Case Report

2 A &B). Immuno histochemistry showed strong immunoreactivity for CD117 and Ki-67 proliferation index of 8% (Fig 2C & D).


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Review of Literature Gastrointestinal stromal tumor (GIST) constitutes only 1% of the non-epithelial tumors of gastrointestinal tract, of which 30-45 % involve small bowel second to stomach (50-60%). Median age of diagnosis is 63 – 66 years (1, 2, 3).

Immuno histochemistry features Most (95%) GISTs express KIT receptor Tyrosine kinase and CD117 positive on special staining. Correlation of KIT mutation and CD117 positivity is not direct. Kit Exon 9 mutations specifically produce small intestinal GISTs (4). Mutation still can be present in CD117 negative patients. Germline KIT mutations and PDGFRA mutations very rarely can give rise to autosomal dominant hereditary GISTs. Other conditions associated with hereditary GISTs are Neurofibromatosis Type 1 (NF1) where it is associated with multiple GISTs of small bowel predominantly in females and Carneys Triad where stomach is predominantly affected along with paraganglionoma and pulmonary chondroma.

Clinical presentation Usual small bowel presentations are abdominal pain, mass, bleeding, bowel obstruction. It can be asymptomatic, detected from images done for other intra-abdominal problem or during endoscopy. Small bowel GIST is usually diagnosed by CT scan of abdomen or during laparotomy or laparoscopy. Contrast enhanced CT gives details regarding the size, extend and evidence of metastasis. MRI is not often useful for small bowel GIST and PET is useful to assess the response to therapy.EUS and guided biopsy is often not accessible to small bowel unlike stomach or large bowel. Open or laparoscopic biopsy may be required for GISTs of small bowel. Pre-operative biopsy is not required for operable GIST

Fig: 3 Flow chart showing risk assessment of GIST small bowel

and percutaneous biopsies can lead to tumor rupture and peritoneal seedling.

Prognosis Site, size and mitotic index are the major factors that determine prognosis (Fig 3)

Treatment Wedge resection with negative margins is the mainstay of treatment for resectable tumors. In small bowel tumors, segmental resection without lymph node dissection is required. Intermediate and high risk patients with CD117 positive tumors require Imatinib treatment after resection. Minimally invasive technique can be used for resection of GIST and series of laparoscopic removal of small bowel GISTs less than 10cm size are reported in the literature. One should be careful while performing these procedures laparoscopically as tumor rupture carries high chance of recurrence. So meticulous technique and minimum handling of the tumor must be employed throughout the procedure. Minimal

access technique have the advantage of small wounds, less pain, early discharge and resumption of work, less blood loss and low morbidity (5,6,7,8).

Adjuvant, neo-adjuvant therapies in primary GIST. Based on data from multi-institutional prospective trials, Imatinib treatment in the adjuvant setting is given to margin positive tumors, intermediate and high risk patients. The accepted regimen of adjuvant treatment is Imatinib tablets 400mg daily for 3 years. Larger tumors and borderline resectable tumors can be treated with neoadjuvant Imatinib and organ preserving surgery such as duodenectomy rather than pancreatoduodenectomy can be done after tumor size reduction (9,10).

5 10 cmIntermediate risk

Any sizeHigh risk

GIST Small bowel

MI5/50HPF

MI5/50HPF

2 cmNo risk

2 5 cmLow risk

10 cmHigh risk


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Metastatic GIST Imatinib 400mg /day is the treatment of choice for metastatic GIST. Dose escalation may be required in progressive disease and Exon 9 mutated tumors. Treatment should be continued till response is maintained or intractable complications of treatment occurs. Sunitinib maleate is another targeted drug which is indicated in progressive disease or toxicity with Imatinib. Cytoreductive surgery is indicated in some cases where targeted therapy has shown tumor reduction (11).

Follow Up Intermediate and high risk patients need follow up in more frequent intervals three monthly for 2years, then 6monthly for 3-5years. Clinical examination and USG/CT abdomen are the mainstay of follow up in small bowel GISTs.

Conclusion Larger GISTs can be safely removed by minimally invasive approach and careful tumor handling technique should be employed during surgery. Specimen extraction without tumor spillage is very important in preventing recurrence. Complete surgical resection, risk assessment, targeted therapy and strict follow up forms the mainstay of treatment. First and second line targeted therapy and cytoreductive surgery has increased OS and DFS of patients with GIST.

References1. Crosby JA, Catton CN, Davis A, et al. Malignant

gastrointestinal stromal tumors of the small intestine: a review of 50 cases from a prospective database. Ann SurgOncol 2001; 8:50–59.

2. Mucciarini C, Rossi G, Bertolini F, et al. Incidence and clinicopathologic features of gastrointestinal stromal tumors: a population-based study. BMC Cancer 2007; 7:230.

3. Nilsson B, Bumming P, Meis-Kindblom JM, et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinibmesylate era – a population-based study in western Sweden. Cancer 2005; 103:821–829.

4. Antonescu CR, Sommer G, Sarran L, et al. Association of KIT exon 9 mutations with nongastric primary site and aggressive behavior: KIT mutation analysis and clinical correlates of 120 gastrointestinal stromal tumors. Clin Cancer Res 2003; 9:3329–3337.

5. Otani Y, Kitajima M. Laparoscopic surgery for GIST: too soon to decide. Gastric Cancer 2005; 8:135–136.

6. Otani Y, Furukawa T, Yoshida M, et al. Operative indications for relatively small (2–5cm) gastrointestinal stromal tumor of the stomach based on analysis of 60 operated cases. Surgery 2006; 139:484–492.

7. Novitsky YW, Kercher KW, Sing RF, et al. Long-term outcomes of laparoscopic resection of gastric gastrointestinal stromal tumors. Ann Surg 2006; 243:738–745; discussion 45–47.

8. Nishimura J, Nakajima K, Omori T, et al. Surgical strategy for gastric gastrointestinal stromal tumors: laparoscopic vs. open resection. SurgEndosc 2007; 21:875–878.

9. Zhan WH, Group CGC. Efficacy and safety of adjuvant postsurgical therapy with imatinib in patients with high risk of relapsing GIST. Proc Am SocClinOncol 2007; 25:abstract 10045.

10. DeMatteo R, Owzar K, Antonescu C, et al. Efficacy of adjuvant imatinibmesylate following complete resection of localized, primary GIST at high risk of recurrence: U.S. intergroup phase II trial ACOSOG Z9000. In: Proceedings of the ASCO Gastrointestinal Symposium; 2008; abstract 8.

11. Raut CP, Hornick JL, Bertagnolli MM. Advanced gastrointestinal stromal tumor: potential benefits of aggressive surgery combined with targeted tyrosine kinase inhibitor therapy. Am J HematolOncol 2006; 5:707–712.


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Carotid Body TumorKrishna Prasad BP, Vijay Jayakrishnan,

Swati C, Shilpa R, Zeeshan L, Brijesh R, Vandana SDepartment of Clinical Radiology, Imaging and Interventional Radiology.

Carotid body tumors are rare neoplastic lesions occurring in the neck arising from the wall of the carotid bulb in the distal common carotid artery.

Lyre sign is seen in carotid body tumor since it fills the crotch of the carotid bifurcation and splays the internal and external carotid arteries.

Figure 1: A - Splayed carotid bifurcation. B - Apollo holding the lyre. C - MRI axial section showing tumor tissue on the right side encasing, and splaying the two carotid vessels. D - Normal carotid bifurcation for comparison

Pseudo Lyre sign can be seen in other tumors causing carotid splaying, like vagal paraganglioma, carotid aneurysm or a rare parathyroid tumor, however they usually neither fill the crotch of the bifurcation nor encase the carotid vessels.

Reference Biswas S, Saha S, Sadhu A. Pictorial assay - Parapharyngeal

space lesion. Indian J Radiol Imaging 2005;15:41-6 Nash R, Farrell R. Pseudo-Lyre Sign. JSCR. 2011 2:2

Medical Image

Address for communication:Dr. Vijay Jayakrishnan, Lead Consultant,Neuro Radiology, Aster Medcity, KochiEmail: [email protected]


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History of Hemodialysis – an OverviewVinod Kumar K, V.N Unni

Aster Nephrology and Urology, Aster Medcity, Kochi

The burden of chronic kidney disease and end-stage renal disease (ESRD) is on the rise worldwide with Diabetic kidney disease being the commonest cause of ESRD. The U.S., Taiwan, and Japan continue to have some of the highest rates, at 369, 361, and 288 per million population in 2010 respectively. The crude and age-adjusted incidence rates of ESRD as per an Indian population-based study are 151 and 232 per million population, respectively ; if validated in other parts of India, it would mean that about 220,000–275,000 new patients need renal replacement therapy (RRT) every year in our country. It is estimated that there are about 55,000 patients on dialysis in India, and the dialysis population is growing at the rate of 10–20% annually (*V. Jha: Kidney International supplements 2013:3; 157-160). The available treatment options for ESRD are hemodialysis, peritoneal dialysis and renal transplantation; hemodialysis is the commonest modality in India.

Figure 1: Thomas Graham and hisexperimental model.

In the Middle Ages, treatments for uremia (Greek word for urine poisoning, or literally, “urine in the blood”) included the use of hot baths, sweating therapies, bloodletting and enemas.Dialysis was first described by Thomas Graham (a chemist in Glasgow University) in 1854. Graham prepared a bell-shaped vessel which had a wide open end closed with a membrane made from an ox-bladder (Figure 1). He filled the bell-shaped vessel with urine and

suspended it inside a larger container, filled with distilled water. After several hours, the bell-shaped vessel was removed. The larger container was heated so that the fluid inside evaporated. Graham showed that the residue in the larger container consisted mainly of sodium chloride and urea, the principal components of urine. This process was termed dialysis and together with Richard Bright (a physician in Edinburgh), proposed that, this would form the basis of a treatment for renal failure. In 1913, John Abel, Leonard Rowntree and B.B. Turner created the first artificial kidney, using Colloidon (material made up of cellulose) tubes held in glass “jacket”. They also used hirudin, found in the blood of leeches as anticoagulant. This device was used in animals and was never tried in humans. In 1924, a German doctor, George Haas performed the first dialysis treatment involving humans (Figure 2). By 1928, Haas had dialyzed additional six patients, none of whom survived. He used Colloidon membrane as the dialyzer and hirudin as anticoagulant. Owing to the severe allergic reactions with insufficiently purified hirudin, he used Heparin as anticoagulant in his seventh and final experiment.

Address for communication:Dr. Narayanan Unni V, MD, DNB, DM, FRCP (Glasgow), FISN.Lead Senior Consultant in Nephrology.Aster Medcity, Kochi, KeralaEmail: [email protected]

Figure 2: Dr. George Haas performing dialysis ona patient at the University of Giessen

Urine

Distilledwater

Ox bladdersemi-permeablemembrane

Medical History

In 1943, Dr. Willem G. Kolff, during the World War II, developed the first safe and useful hemodialysis machine for treating patients with renal failure.When he was working as a resident in late 1930s at the University of Groningen Hospital, he watched helplessly as a young man died slowly of kidney failure. Kolff decided to find a way to make


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Figure 5: Alwall DialyzerFigure 3: Dr. Willem Kolff and Kolff ’srotating drum kidney

a machine that would do the work of the kidneys. The young doctor was inspired by the work done by John Abel in 1913 about hemodialysis on animals, and he became committed to the development of an artificial kidney. The Kolff kidney (Figure 3) used a 20-meter long tube of cellophane sausage casing as the membrane. The tube of casing was wrapped around a slatted wooden drum. Run by an electric motor, the drum spun in a tank filled with dialysate. As the membranous tubes passed through the bath, the uremic toxins would pass into the liquid in the bath. During the course of the next two years, he treated 16 patients with acute kidney failure, but had little success. His first major success came in 1945, when a 67 year-old woman in uremic coma regained consciousness after 11 hours of hemodialysis with Kolff ’s dialyzer.

Kolff ’s rotating drum underwent significant technical improvement in Peter Brent Brigham hospital, Boston during the Second World War and the modified machines became known as the Kolff-Brigham kidney (Figure 4). A sausage casing (cellulose) membrane was still wrapped around a drum. This time, it was connected to latex tubing that could be attached to the patient’s bloodstream. As with the first model, the drum rotated in a container with the dialysate fluid. This was used to save the lives of many soldiers who had post-traumatic acute renal failure during the Korean War.

Figure 4: Kolff-Brigham Dialysis Machine

In 1947, Dr. Nils Alwall developed a creative machine called the Alwall kidney (Figure 5) in Sweden. The machine was comprised of a barrel placed in a stainless steel canister. This enabled positive pressure to be applied and hence fluid could be removed. Thus developed the concept of combined processes of dialysis and ‘ultrafiltration’ (Fluid removal).

In 1960, Norwegian doctor Fredrik Kiil, presented the dialyzer where the membrane used was Cuprophan. Three or more Kiil (Figure 6) boards were used with two sheets of membrane sandwiched between each pair of boards. Grooves in the boards directed the blood between the layers of membrane-and the dialysate outside the membrane envelope in opposite directions from one end of the boards to the other. When AV shunt was used, blood could be pumped through the device with blood pressure only and hence no blood pump was needed. Excess fluid was removed by the use of negative pressure on the dialysate effluent line. Kiil dialyzers were in use in some clinical units until the end of 1990’s.


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Another major breakthrough in the field of hemodialysis was the development of the hollow-fiber dialyzer (Figure 7) by Richard Stewart in 1964. Richard Stewart was given a grant to explore medical uses of cellulose acetate capillary fibers. His group thought the fibers could be used to make an artificial kidney. The original “Capillary Kidney” showed that wastes could be selectively removed from the blood, as well as excess water. This technology replaced the until-then traditional membranous tubes and flat membranes with a number of capillary-sized hollow membranes. The typical hollow-fiber dialyzers of today are equipped with a more effective and better-tolerated membrane made primarily from synthetic polymers (Polysulfone, polyacrylonitrate and others).

Figure 7: Capillary Artificial Kidney(Hollow Fiber Dialyzer).

Figure 8: Teflon dialysis cannulas (Shunts).

Vascular access for Hemodialysis: In the earlier days, typically a glass cannula or tube would be surgically placed in a blood vessel. Owing to the complex nature of the surgery coupled with the fact that cannula could not remain in place for a significant period of time, newer techniques evolved. In 1960, Wayne Quinton, a biomedical engineer, with the help of Scribner, developed a permanent access using Teflon tubing. This material was successful because of non-stick properties that prevented the blood from adhering to it and clotting.

Figure 6: Kiil Dialyzer

With the creation of a reusable vascular access called the Scribner shunt, dialysis treatments became easier to perform thereafter. Dr. Belding Scribner of Seattle Washington, used a U-shaped Teflon tube that routed blood from an artery back to a vein (Scribner Shunt). The shunt protruded out from the skin and was attached to the blood tubing. When the shunt was not in use, caps were placed over the tubing. With this new shunt, chronic kidney failure patients had access to hemodialysis. The access could remain in place for about two months. In 1962, with the introduction of more flexible material, the shunts had an extended life span anywhere from several months to several years. Clyde Shields, in Seattle became the first chronic hemodialysis patient, in whom the shunt was implanted, and the dialysis treatments allowed him to live an additional eleven years.

Figure 9: Dr. Belding Scribner andScribner shunt in the ankle.


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In 1961, Stanley Shaldon from London, faced the problem of finding a surgeon willing to operate on the radial artery and cephalic vein to introduce cannulae for circulatory access. To become independent, Shaldon introduced hand-made catheters into the femoral artery and vein by the percutaneous Seldinger technique for immediate vascular access. Over time, vessels in different sites were used, including the subclavian vein. Shaldon concluded: ‘Eventually, veno-venous catheterization was preferred because the bleeding from the femoral vein was less than from the femoral artery when the catheter was removed’.In 1969, after the first use of the subclavian route for hemodialysis access by Shaldon, this technique was adapted by Josef Erben from former Czechoslovakia, using the infraclavicular route. In addition, this catheter permitted to control central venous pressure in dehydrated, oliguric hemodialysis patients. During the following two decades the subclavian approach became the preferred route for temporary vascular access by central venous catheterization. At present, internal jugular vein is the preferred site for temporary vascular access placement, as it was realized that subclavian vein catheter was associated with a higher incidence of venous thrombosis.

The most decisive breakthrough in the field of vascular access came in 1966 when Brescia, Cimino and their colleagues joined an artery in the arm with a nearby vein allowing the vein to get “arterialized” (caused it to swell). Needles could then be more easily placed in this vein, which lay beneath the skin and thus allowed repeated punctures. The Arteriovenous (AV) fistula remains the access of choice for dialysis patients, and some AV fistulas have lasted for more than 30 years.

The year 1972 saw the introduction of three new graft materials, one biologic and two synthetic. A modified bovine carotid artery biologic graft, a product of research by D.M.L. Rosenberg, was introduced for construction of vascular access in eight hemodialysis patients by Joel L. Chinitz. It was the first xeno-graft and received some acceptance during the 1970s. In 1976, L.D. Baker Jr from USA, presented the first results with expandable polytetrafluoroethylene (PTFE) grafts in 72 hemodialysis patients. The majority of these grafts were 8 mm in diameter. Irving Dunn from USA had chosen a dacron velour vascular graft for creation of AV bridge grafts, initially in animal experiments and then in a uremic female patient. Subsequently, this material did not yield satisfactory results for vascular access.

Figure 10: Brescia-Cimino Arteriovenous Fistula

Radial Artery Cephalic Vein

Figure 11: Loop AV graft made of PTFE.


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Catheters for Hemodialysis Two types of hemodialysis catheters are currently available; non-cuffed, non-tunneled catheters for immediate hemodialysis and cuffed, tunneled catheters for long term dialysis. The introduction of the polytetrafluoroethylene (PTFE) graft and the cuffed double lumen silicone catheter were the only new changes that occurred in the field of vascular access in the last few years.

Hemodialysis equipment – recent developments The major developments over the past four decades is related to improvements in membrane biocompatibility and dialyzer design, volumetric control, sophisticated monitoring systems that provide online clearances, isothermal dialysis, high flux membranes and convective modalities such as hemofiltration and hemodiafiltration.

History of Hemodialysis in India In India, the first successful hemodialysis was performed in Christian Medical College, Vellore in the year 1961. It was performed using Kolfftwin-coil artificial kidney, donated by the Christian Mission of USA. The first patient to receive dialysis was His Excellency Shri Gopeshwar Prasad Sahi, the erstwhile Maharaja of Hathwa, in the old state of Bihar, who had developed “chronic uremia”.Dr. Satoru Nakamoto, who was sent by Dr. Willem

Figure 12: a) Non-cuffed catheter, b) Cuffed catheter.

Figure 13: Present Dialyzers and Dialysis machine.

Figure 14: First Kolff Twin-coil Dialysis Machine and Kiil Dialyzer used in PGIMER

(Courtesy Dr. K.S. Chugh)

Kolff supervised the initial few sessions of dialysis, and trained Dr Philip Koshy, then Professor of Medicine at the CMC, about the technique of dialysis. In 1963, the first hemodialysis in North India was performed at Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, using Kolff twin-coil machine. Dialysis bath was prepared by adding preweighed chemicals to the 100-L tank, which contained warm tap water and was maintained at body temperature by a heater incorporated within.


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In 1968, Dr. Kripal S. Chugh, after his return from London, started a long-term dialysis program at PGIMER using 2 Kiil dialyzers. AV shunts made of 2 sialistic tubes were used as access. They designed a steel tank that was placed at a height of 10 feet, and the dialysis fluid was fed to 2 Kiil dialyzers by gravity. Only temperature of the dialysis fluid was monitored initially, later they acquired Lucas monitoring machine.

Future expectationsWearable artificial kidney After over a decade of development, Dr. Victor Gura and Dr. David Geffen designed wearable artificial kidney, which is a miniature dialysis machine small enough to be worn like a tool belt and is connected to the patient by means of a catheter. It has been granted approval for human testing in the United States by the FDA.

Figure 15: Wearable Artificial Kidney.

Bioartificial Kidney (BAK) Conventional dialysis replaces only the filtrative function of the kidney. The concept of Bioartificial kidney is designed to replace the metabolic, endocrine and immunomodulatory functions of the kidney. BAKs combine a conventional hemofilter in series with a bioreactor unit containing renal epithelial cells derived from the proximal tubule using tissue engineering techniques, which are based on the ability to expand stem or progenitor cells in tissue culture. Further research is needed to produce a wearable artificial kidney which would sense the volume and electrolyte composition of the blood, and remove excess water and solutes from the blood; in addition to this excretory function, this device needs to perform the hormonal and secretory function of the normal human kidney.

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