Vol. 11 No. 2 January 2017 ISSN: 0972–1096 Journal ofupchapterapi.com/uploaded/journalPdf/journal_pdf_2_5204.pdf · 2017. 5. 8. · JOURNAL OF INTERNAL MEDICINE OF INDIA• JANUARY

www.groupexcelindia.com

91 A, Ground Floor, Pratik Market, Munirka, New Delhi-110067Call: +91-11-2671 1755/ 2755/ 3755/ 5755• Fax: 011-2671 6755e-mail: [email protected] • Web: www.groupexcelindia.com

Publishing ConsultancyD

esigned and Printed by: E

xcel Printing U

niverse, e-mail: printing@

groupexcelindia.com, W

ebsite: ww

w.groupexcelindia.com

RNI No.: 69152/98

Journal ofINTERNAL MEDICINE OF INDIA

Vol. 11 No. 2 January 2017 ISSN: 0972–1096

OFFICIAL PUBLICATION OF ASSOCIATION OF PHYSICIANS OF INDIA – U.P. CHAPTER

U.P. CHAPTER

w w w . u p j i m i . o r g

JIMIEditor-in-Chief Dr. S. Chakravorty

JIMIJOURNAL OF INTERNAL MEDICINE OF INDIA

Associate Editors Prof. (Dr.) Sarita Bajaj • Prof. (Dr.) Om Kumari Gupta

Assistant Editors Prof. (Dr.) Madhukar Rai • Prof. (Dr.) Kauser Usman

Editorial Secretary Dr. S.K. Plaha • Dr. A.K. Shukla • Dr. Meenakshi Jain

Editor-in-Chief: Dr. S. Chakravorty


Dr. Anuj Maheshwari Dr. N.K. SoniDr. Virendra AtamDr. Arvind MishraDr. K.K. SawlaniDr. Praveen Kumar BassDr. R.R. SinghDr. K.C. LohaniDr. Jalees FatimaDr. Veerendra SinghDr. Mahim Mittal

Dr. Balvir Singh

Dr. Sudhir Agarwal

Editorial Board

Dr. Sanjay Singh

Dr. A.K. Singh

Dr. Subodh Chandra

Dr. Abha Gupta

Dr. Amitesh Aggarwal

Dr. Saurabh Shrivastava

Dr. S.K. Sahoo

Dr. Atul Mehrotra

Dr. G.C. Vaishnava

Dr. R.K. Gattani

Dr. Sanjay Mahajan

JOURNAL OF INTERNAL MEDICINE OF INDIA• JANUARY 2017 • VOL. 11 • NO. 2 • RNI No. 69152/98

JIMI • JANUARY 2017 • VOL. 11

Editorial & Publishing OfficeDr. S. ChakravortyT-21, SECTOR-11, NOIDA-201301 (UP). INDIAE-mail: [email protected]: 9810210479

Subscription InformationUttar Pradesh Journal of Internal Medicine of India (ISSN: 0972-1096). For 2017, Volume 11(2 issue) is scheduled for publication. Subscription prices are available upon request from the publisher or from UP Journal of Internal Medicine of India or from this Journal website (www.upjimi.org), or contact UP JIMI Customer Service Centre: T-21, Sector-11, Noida-201301 (UP) India.Tel. (0120-2538432, +91 9810210479)E-mail: [email protected]

Advertisements

E-mail: [email protected]

JOURNAL OF INTERNAL MEDICINE OF INDIA• JANUARY 2017 • VOL. 11 JOURNAL OF INTERNAL MEDICINE OF INDIA• JANUARY 2017 • VOL. 11

JIMI • JANUARY 2017 • VOL. 112 JIMI • JANUARY 2017 • VOL. 11 3

Chairman Dr. Sarita Bajaj Chairman-Elect Dr. Virendra atam Vice-Chairman Dr. Kauser Usman Dr. Veerendra Singh Hon.Seceretary Dr. D. Himanshu Treasurer Dr. S. Chaudhary JointSecretaries Dr. Anupam Wakhlu Dr. S. Chakravorty

Governing Body Members

Dr. Jalees FatimaDr. Sanjay TandonDr. Anuj MaheshwariDr. Abha GuptaDr. Anjum ParvejDr. Jaya Chakravorty

Co-opted Members

Dr. R.R. GuptaDr. K.K. SawlaniDr. Kailash Kumar GuptaDr. A.K. SinghDr. Manoj MathurDr. N.K. SoniDr. Om Kumari GuptaDr. Sudhir Agarwal

Governing Body ASSOCIATION OF PHYSICIANS OF INDIA

NOIDA CHAPTER

Governing Body ASSOCIATION OF PHYSICIANS OF INDIA

UP CHAPTER

PatronDr. (Prof.) B.C. BansalDr. (Prof.) Om Kumari GuptaDr. S.K. Plaha

FormerChairmanDr. B. GandhiDr. K.C. SoodDr. Subodh ChandraDr. G.C. Vaishnava

ChairmanDr. S. Chakravorty

ViceChairmanDr. Kunal Das

SecretaryDr. A.K. Shukla

JointSecretaryDr. Amitesh AggarwalDr. Saurabh Srivastava

TreasurerDr. Meenakshi Jain

ScientificAdvisorDr. Rakesh PrasadDr. L.K. JhaDr. Amitabh Yaduvanshi

CoreCommitteeMemberDr. Gulab GuptaDr. Ajay AgarwalDr. S.K. SahooDr. Yogesh ValechaDr. N.K. SharmaDr. Kiran SethDr. Amit GuptaDr. Vandana Garg



Dear All,Wish you a very happy and prosperous New Year

2017.

2016 had been a very eventful year where in people suffered from myriads of health related and political

issues. Citizens of India were once again exposed to suffering from health service related constraints arising out of several viral epidemics. The complications of viral diseases lead to tremendous prolonged suffering which continued till end of the year. Majority of these diseases were mosquito borne and some were spread by person to person contact or fomites. It becomes imperative to disseminate knowledge of such ailments amongst us in order to manage such catastrophies well in future.

The onset of rainy reason saw a large number of chikungunya fever cases pouring in. Variety of complications of dengue fever and chikungunya fever were also noted. Majority of reported deaths were caused by complications and immune compromised state and not by the viral infection itself. Aged and children were most at risk of developing serious complications and many of them developed systemic and neurological problem. The virus is not known to be neurotropic but cases of myeloradiculopathy, transverse myelopathy, Guillain Barre Syndrome has been reported1. The commonest and most debilitating complications of CHIK-V infection was in elderly patients who developed chronic arthralgia/arthritis.

Clinically they presented with highly tender swollen joints mimicking rheumatoid arthritis.

It has been seen that those patients who developed chronic arthritis were usually elderly and had a much higher viral load during the acute phase. The anti viral immune response suggested by high level of IFN α mRNA in the peripheral monocytes and circulating IL-12 persist for months in those patients having features of chronic arthritis. The chikungunya Virus mRNA protein persists in synovial tissue and associated with fibroblast hyperplasia angiogenesis leading to cell apoptosis and tissue lesions as evidenced by high levels of matrix metalloproteinases. Those immunecytopathogenic mechanisms contribute to development of chronic arthralgia/arthritis1-2.

The spectrum of post chikungunya musculoskeletal disorders includes multiple tendinitis and tenosynovitis, plantar fasciitis, oedematous polyarthralgia & tunnel syndrome. 5% of people developed chronic inflammatory rheumatism mostly rheumatoid arthritis. These findings require early treatment with DMARD to control the inflammatory process, reduce bone erosion and prevent deformity 3-4.

Hydroxy chloroquine has been used commonly in rheumatoid arthritis and lupus because of its anti-inflammatory and immunosuppressive properties. The same property has been utilized in patients of Chikungunya who developed post Chik-V arthritis/Arthralgia. The precise anti-inflammatory mechanism of HCQ is not known and is probably related to alkalinisation of endosomal organelles in immune cells. A similar anti inflammatory effect has also been seen in patients of diabetes coexistent with rheumatoid arthritis. It improves insulin secretion and peripheral insulin sensitivity. Also inhibits insulin degradation in hepatocytes and lower HbA1C and LDL cholesterol in Type 2 diabetes subjects. HCQ has been shown to reduce the incidence of diabetes among patients with rheumatoid arthritis and lupus and to improve glycaemia in patients with rheumatic disorder and diabetes5-6.

Studies have shown that macrophages release cytokines and create a pro-inflammatory environment that blocks insulin action, contributing to the development of insulin resistance, β cell damage and eventually Type-2 diabetes. The main cytokines involved in the pathogenesis of T2DM are IL-1β TNF α, IL-6 and MCP-1. TNF α & IL-6 alters the insulin sensitivity by affecting crucial steps in its signalling pathway. The expression of these inflammatory cytokines increases in obese diabetics and is accompanied by systemic inflammation, insulin resistance and progression of diabetic nephropathy. HCQ lower the pancreatic levels of IL-1β, IL-6, TNF α & TGF-β, and MCP-1, thereby reducing the pro-inflammatory environment that leads to development of insulin resistance and subsequently diabetes mellitus7-8. Sharma et al. in their study on a cohort of rheumatoid arthritis patient have shown that treatment with hydroxychloroquine was independently associated with a 72 % reduction in all incident CVD events and a 70% reduction in the risk of incident composite CAD, stroke and TIA7.

References1. “Emergence of Clinical Insights into the Pathology of

Chikungunya Viral Infection”, Expert Rev Anti Inject Therapy, 2010, Vol. 8(9), pp. 987–996.

2. “Post Chikungunya Rheumatoid Arthritis: Saint Martin”, Emerging Infection Disease, Vol. 21, No. 3, March 2015.

3. Anti-inflammatory Agent in the Treatment of Diabetes and its Vascular Complications, Diabetes Care, 2016, Vol. 39, pp. 5244–5252.

4. Pollack, Rena M. and Donath, Marc Y. (2016), “Anti-inflammatory Agents in the Treatment of Diabetes and Its Vascular Complication”, Diabetes Care, Vol. 39(Suppl. 2), pp. S244–S252.

Editorial


JIMI • JANUARY 2017 • VOL. 114 JIMI • JANUARY 2017 • VOL. 11 PB

5. Wasko, Mary Chester M. and mClure, Candace K., (2015), “Antidiabetogenic Effects of Hydroxychloroquine on in Insulin Sensitivity and Beta Cell Function:a Randomised Trial”, Diabetologia 2015, 22 April.

6. Gerstein, Hertzel C. and Kevin, E. (2001), “Thorpe the Effectiveness of Hydroxychloroquine in Patients with Type Diabetes Mellitus who are Refractory to Sulfonylureas a Randomized Trial”, Diabetes Research and Clinical Practice, Vol. 55, 2002, 2 March.

7. Sharma, Tarun S.M.D. and Mary Chester M. (2015), “Hydroxychloroquine Use is Associated with Decreased Incident Cardiovascular Events in Rheumatoid Arthritis Patients”, 29 October, Journal of American Heart Association: 2015.

8. Abdel-Hamid, Ahmed A.M. and El-Firgany, Alaa El-Din L. (2016), “Hydroxychloroquine Hindering of Diabetic Isletopathy Carries its Signature on the Inflammatory Cytokines”, Journal of Molecular Hystology, 11 Feb 2016.

DISCLAIMERThe content and context of the papers are written by authors and compiled in this volume. The originality and authenticity of the papers and the interpretation of information and views expressed therein are the sole responsibility of the authors. The publishers or editors do not take any responsibility for the same in any manner. Although every care has been taken to avoid errors and omissions, JIMI is being published on the condition and undertaking that the information given in this Journal is merely for reference and must not be taken having authority of, or binding in any manner on the editors or publisher.

JIMI


JIMI • JANUARY 2017 • VOL. 11PB JIMI • JANUARY 2017 • VOL. 11 5

ContentsORIGINAL ARTICLE

1. Effect of Yoga Therapy on Heart Rate and Blood Pressure in Coronary Artery Disease Patients

Priyank Rastogi, Abha Gupta and Tungvir Singh Arya 7

2. An Unusual Cause of Generalized Dystonia Amenable to Medical TherapyMani Gupta, Abha Gupta and Shailesh Singh 12

3. A Prospective Study of Outcome of Malaria—Associated Acute Kidney InjuryHarender Singh, K.K. Pahwa and Ila Pahwa 14

4. Anti-Inflammatory Effect of Statins in Chronic Obstructive Pulmonary DiseaseShalini Sharma, Ila Pahwa and Jayant Mudgal 19

REVIEW ARTICLE

5. Acute Cerebellar AtaxiaAnjum Mirza Chughtai, Muhammad Uwais Ashraf and M.R. Ajmal 22

6. Abnormal MovementsAnjum Mirza Chughtai, Muhammad Uwais Ashraf and M.R. Ajmal 27

7. Diabetic Charcot OsteoarthropathyBhandari S., Agrawal N.K. and Nath M. 31

8. Glycemic Variability and its Clinical ImplicationsDr. Narsingh Verma and Dr. Anuj Maheshwari 35

9. Renal Artery Stenosis—An UpdateDr. Prashant T. Upasani and Dr. Purshotam Lal 39

CASE REPORTS

10. Myelitis: A Rare Complication of Chikungunya FeverKiran Seth, S. Chakravorty, Kapil Singhal, Sayeed Amir, Prashant Arun and Piyush Sood 47

Medical History-Autophagy 51Knowledge forum-RDW 55Announcement-UPDA & UP RSSDI 59



Introduction

Coronary artery disease (CAD) is a major cause of mortality and morbidity all over the world. India is

undergoing a rapid health transition with rising burden of CAD. There has been an alarming increase over the past two decades in the prevalence of CAD and cardiovascular mortality in India and other south Asian countries. With increasing understanding about the role of stress, anxiety and depression in causation of lifestyle related disorders like CAD, there has been a renewed interest in age old remedies like yoga among medical practitioners and researchers alike in their management.

Yoga is a systematic way of lifestyle, health and spirituality that evolved over a period of some 5000 years in Indian peninsula. The word yoga means “union” in Sanskrit and implies the union occurring between the mind, body and spirit. The mainstay of yoga practice involves the adoption and maintenance of specific body postures and associated controlled breathing techniques.

Heart rate is a predictor of cardiovascular and all-cause mortality in the general population and in patients with cardiovascular disease.[1] Heart rate affects basically all stages of the cardiovascular disease and has therefore evolved as a relevant risk marker and goal of therapy in cardiovascular prevention and disease.[²] Increased resting heart rate multiplies risk and interferes at all stages of the cardiovascular disease continuum

initiating from endothelial dysfunction and continuing via atherosclerotic lesion formation and plaque rupture to end-stage cardiovascular disease. In the Framingham study, cardiovascular mortality increased progressively with resting heart rate in a population free from cardiovascular disease. The effect of heart rate on mortality was independent of other cardiovascular risk factors.[³] The prognostic importance of resting heart rate for morbidity and mortality in patients without cardiovascular disease also applies to populations with established CAD and after myocardial infarction. Studies such as CASS and Beautiful demonstrated a positive association between increased resting heart rate and cardiovascular mortality.[4,5]

Similarly, blood pressure also has an important bearing on the outcomes of CAD. The totality of evidence indicates a strong association between blood pressure and CAD. As per 2015 American Heart Association (AHA) scientific statement on blood pressure in CAD, for those patients who have already experienced a stroke, myocardial infarction (MI) or transient ischemic attack, or those who have other cardiovascular conditions, a blood pressure target of less than 130/80 mm Hg is reasonable in preventing the adverse outcomes of CAD including mortality.[6]

Aims and Objectives of the StudyAgainst this backdrop, studies are being conducted to explore the role of age-old Indian concept of yoga as a viable, inexpensive and relatively safe tool in the management of CAD worldwide The objective of this study was therefore to find out whether yoga has a positive effect on the blood pressure and heart rate which in turn have a significant bearing on the survival of patients of CAD.

1Assistant Professor of Medicine, Department of Medicine, North DMC Medical College and Hindu Rao Hospital, Delhi, India2,3Professor, Department of Medicine, LLRM Medical College Meerut, UP, IndiaE-mail: [email protected], [email protected]

Effect of Yoga Therapy on Heart Rate and Blood Pressure in Coronary Artery Disease Patients

Priyank Rastogi1, Abha Gupta2 and Tungvir Singh Arya3

ABSTRACTObjectives: The study was conducted to find out the effect of yoga on heart rate and blood pressure in CAD patients. Methods: This prospective, controlled study included the CAD patients between the ages 30 to 70 years who were randomised to yoga group (group A, n = 51) and control group (group B, n = 51). The yoga group patients were prescribed a family based yoga programme including dietary modifications, stress management and asanas in addition to the conventional drug treatment for CAD. The control group received conventional drug therapy alone. The patients were assessed at baseline and thereafter, at the end of 3 and 6 months.Results: At the end of six months group A patients showed significantly greater improvement in clinical parameters like Heart rate (reduction of 9.56% from the mean baseline of 87.39; independent t-test p-value < 0.01), Systolic BP (8.60% reduction from the mean baseline of 130.43; independent t-test p-value = 0.02) and Diastolic BP (reduction of 4.40% from the mean baseline of 83.00; independent t-test p-value = 0.01) vis-à-vis the control group B patients.Conclusions: In the present study, we witnessed a substantial and significant beneficial effect of yoga on clinical parameters like heart rate, systolic BP and diastolic BP in CAD patients.Keywords: Yoga, Coronary Artery Disease, Blood Pressure, Heart Rate

Original Article



Research MethodologyThe study was a prospective, controlled trial in which patients of angina and MI were enrolled and followed for six months conducted at Department of Medicine, LLRM Medical College, Meerut.

The Literature Search StrategyThe survey of literature was done using resources in National Medical Library, New Delhi and the library of LLRM Medical College, Meerut and documents, publications and correspondence with some of the leading yoga research institutes in India like Morarji Desai National Institute of Yoga (MDNIY), New Delhi and internet resources. Among the internet resources, relevant literature on ‘yoga in cardiac disease’, ‘cardiac health’ were extensively referred. The citations of relevance were selected and reviewed.

Inclusion CriteriaPatients of Stable Angina and post MI, Patients of both sexes between the ages of 30 and 70 years, Patients who consented for completing the entire span of project within six months, Patients who were mentally and physically fit up to a minimum level required to participate in the study were included.

Exclusion CriteriaPatients aged less than 30 years, Patients with history of acute MI in recent past (within last 2 months) and unstable angina pectoris, Patients with clinically significant Cardiac failure, Patients with LV Ejection fraction (LVEF) < 20%, Patients who had already undergone coronary angioplasty or bypass surgery, Any substance abuse, mental illness or conditions, which in the opinion of investigator would make it difficult for the potential participant to participate in the intervention were excluded.

Detailed history was recorded and thereafter, all the patients participating in the study were subjected to thorough clinical assessment and routine investigations. The patients were randomly assigned to one of the following two groups with enrolment of 51 patients in each group:

Group A (Study Group/ Yoga Group): Patients of MI and angina on conventional drug treatment for CAD and undergoing yoga therapy.

Group B (Control Group): Patients of MI and angina on conventional drug treatment for CAD and not undergoing yoga therapy.

Patients in the study group were advised strict yoga based lifestyle modification. Concept of yoga which includes correct routines and positive attitudes, yogic

diet were explained to the participants. They were trained in yogic techniques and asanas useful for heart like tadasana, padhastasana, vajrasana, shashankasana, pawanmuktasana, shavasana and pranayama. Techniques and illustrations of these alongwith the necessary precautions were given to each participant in the form of yog pustika, published in Hindi, the local language. Participants were told to practice yoga regularly for atleast 60–80 minutes a day. All asanas were not mandatory (especially for patients with LVEF between 20–30%). Patients with LVEF 20–30% were prescribed only mild asanas which they could perform without discomfort.

Patients were assessed at baseline and at the end of six months for parameters like Heart rate, Systolic BP and Diastolic BP. Mean of each of these parameters and standard deviation alongwith change on these parameters were calculated for each group at baseline and at 6 months. Significance of difference within each group was calculated by paired t-test and between yoga and control groups was calculated by independent t-test. The significance level of 5% has been considered for reporting the results. The calculations were done either manually or using SPSS (Statistical Package for Social Sciences) software.

A total of 102 patients were randomly allocated to either Group A (Study Group/ Yoga Group) or Group B (Control Group). A fairly large number of them (91 patients) completed the study. While in Group A (patients undergoing yoga therapy in addition to conventional drug treatment for CAD), out of 51 patients who were enrolled, 46 patients (90.2%) completed 6 months follow up and the rest were lost in the follow up, in the Group B (patients on conventional drug treatment for CAD not undergoing yoga therapy), out of 51 enrolled patients, 45 patients (88.2%) completed their 6 months follow up (Table 1).

Table 1: Study and Control Group Distribution

Group Patients Enrolled

Patients who Completed 6 Months Follow up

Group A (Study Group) 51 46 (90.2%)Group B (Control Group) 51 45 (88.2%)Total 102 91

ResultsThe baseline characteristics of the patient population

are detailed in Table 2. It can be seen from the Table that there was no significant difference between the study and the control groups at baseline in any of the characteristics examined (independent t-test p-value > 0.05) and thus it can be inferred that both the groups reflect the same population.



Table 2: Baseline Characteristics of Study and Control Groups

S. No.

Parameter Study Group

Control Group

P-value(Independent

t-test)1. Mean heart

rate (/mt)87.39 + 9.95 88.36 +

9.370.64

2. Mean systolic BP (mmhg)

130.43+20.96 130.93 + 24.73

0.92

3. Mean diastolic BP (mmhg)

83.00 + 9.93 83.60 + 10.86

0.78

4. Mean age (years)

52.89 + 8.83 54.36 + 11.64

0.50

5. Percentage of males

76.09 73.33 0.76*

6. Percentage of females

23.91 26.67 0.76*

NYHA = New York Heart Association; BP= Blood Pressure; *= Chi-square Test P-value

Heart RateIt can be seen from Table 3 that there is a significant reduction of 9.56% (paired t-test p-value < 0.05)) in mean heart rate in the patients in the yoga group (Group A) at the end of six months. In the control group patients also, there was a statistically significant but lesser improvement of 4.89% from baseline value (paired t-test p-value < 0.05). It is also evident from the same Table that while at baseline, there was no statistically significant difference between the yoga and control groups (independent t-test p-value > 0.05), the difference became significant at the end of six months (independent t-test p-value < 0.05). This can be attributed to the significantly beneficial impact of yoga on heart rate.

Table 3: Heart Rate at Baseline and 6 Months

Group Pre Study (Baseline)

Mean Heart Rate/mt

Post Study(at 6 Months)Mean Heart

Rate/mt

Mean Difference

Difference in

Percentage

P-value within

the Group (Paired t-test)

Yoga group (Group A)

87.39 + 9.95 79.04 + 5.96 -8.35 -9.56% <0.001

Control group (Group B)

88.36 + 9.37 84.04 + 8.24 -4.32 -4.89% 0.001

P-value(independent t-test)

0.64 0.001

Systolic Blood PressureIt can be seen from Table 4 and Fig. 1 that there is a significant reduction of 8.59% (paired t-test p-value < 0.05) in systolic BP in the patients in the yoga group (Group A) at the end of six months. In the control group patients also, there was a statistically significant but lesser reduction of 4.31% from baseline value (paired t-test p-value < 0.05). It is also evident from the same Table that while at baseline, there was no statistically significant difference between the yoga and control groups (independent t-test p-value > 0.05), the difference became significant at the end of six months (independent t-test p-value < 0.05). This can be attributed to the significantly beneficial impact of yoga on systolic BP.

Table 4: Systolic BP at Baseline and 6 Months


Mean Systolic BP

(mmhg)

Post Study(at 6 Months)

Mean Systolic BP

(mmhg)

Mean difference

Difference in

Percentage

P- value within



130.43+20.96 119.22+12.25 -11.21 -8.59% <0.001


130.93+24.73 125.29+12.67 -5.64 -4.31% 0.04


0.92 0.02

Diastolic Blood PressureIt can be seen from Table 5 and Fig. 1 that there is a significant reduction of 4.40% (paired t-test p-value< 0.05) in mean diastolic BP of the patients in the yoga group (Group A) at the end of six months. In the control group patients, there was no statistically significant change from baseline value (paired t-test p-value > 0.05). It is also evident from the same Table that while at baseline, there was no statistically significant difference between the yoga and control groups (independent t-test p-value > 0.05), the difference became significant at the end of six months (independent t-test p-value < 0.05). This clearly brings to fore the significantly beneficial impact of yoga on diastolic BP.

Table 5: Diastolic BP at Baseline and 6 Months


Mean Diastolic BP

(mmhg)

Post Study(at 6 Months)

Mean Diastolic BP

(mmhg)

Mean Difference

Difference in

Percentage

P- value within



83.00 + 9.93 79.35 + 5.02 -3.65 -4.40% 0.003


83.60 +10.86 83.11 + 7.60 -0.49 -0.59% 0.55


0.78 0.01

Fig. 1: Improvement in Blood Pressure in Yoga and Control Groups at 6 Months



DiscussionDuring the last decade, numerous studies have been conducted to evaluate the effect of exercise training on clinical parameters like heart rate and blood pressure. These studies have demonstrated beneficial effect of exercise training. However, studies examining specifically the role of yoga on these parameters in the patients of CAD including post MI patients have been limited.

It was with the landmark study conducted by Ornish et al. in 1983 that the world started to look into the role of yoga and lifestyle modification on cad with a renewd interest.[7] Besides, Tulpule and Tulpule, 1980 reported the beneficial effect of yogic asanas in controlling blood pressure and cholesterol levels in patients of CAD.[8]

Schmidt et al., 1997 and Selvamurthy et al., 1998 very convincingly demonstrated that regular yogic practice is as effective in controlling hypertension as medical therapy.[9,10] It was further substantiated in a study conducted by Murugesan et al., 2000.[11]

Yoga therapy mediated reduction in heart rate and blood pressure indicate a shift in the balancing components of autonomic nervous system towards the parasympathetic activity which was reported by Santha Joseph et al.[12] and Anand BK et al.[13] This modulation of autonomic nervous system activity might have been brought about through the conditioning effect of yoga on autonomic functions and mediated through the limbic system and higher areas of central nervous system was reported by Selvamurthy et al.[14] Regular practice of yoga increases the baroreflex sensitivity and decreases the sympathetic tone, thereby restoring blood pressure to normal level in patients of essential hypertension was reported by Vijaya Lakshmi et al.[15] Yoga based guided relaxation has also helped in reduction of sympathetic activity with reduction in heart rate, oxygen consumption and increase in breath volume thus facilitating protection against angina and myocardial infarction as reported in a study conducted by Vempati and Telles, 2000.[16]

The results of our study are consistent with those of the above mentioned studies. The patients in the yoga group vis-à-vis control group showed a significant improvement in clinical parameters like Heart rate (reduction of 9.56% from the mean baseline of 87.39; independent t-test p-value < 0.01), Systolic BP (8.60% reduction from the mean baseline of 130.43; independent t-test p-value = 0.02) and Diastolic BP (reduction of 4.40% from the mean baseline of 83.00; independent t-test p-value = 0.01) at the end of 6 months of study.

ConclusionYoga therapy (in conjunction with conventional drug treatment for CAD) has a significant beneficial effect on clinical paramenters like heart rate, systolic BP and diastolic BP in patients of CAD.

Limitations of the Study This study is a modest attempt in one of the important areas of role of yoga in heart disease and it hopes to encourage further research in this field. In our study, we could not include the parameters like levels of plasma catecholamines, leukotrienes, IL-1, IL-6 and TNF which are likely to be responsible in the pathogenesis of CAD. This can form a subject of future study and may help to further explore the mechanism of effect of yoga in CAD.

Furthermore, CAD has a chronic course and studies may be done over longer period of time to demonstrate the effect of yoga therapy on natural history of the disease. We recommend further large scale and multi-centric trials for longer follow up with intensive investigative approach to calibrate the benefits of yoga therapy in patients of angina and MI.

Acknowledgement All patients who participated in the study.

References1. Custodis, Florian, Reil, Jan-Christian, Laufs, Ulrich and

Böhm, Michael (2013), “Heart Rate: A Global Target for Cardiovascular Disease and Therapy along the Cardiovascular Disease Continuum”, Journal of Cardiology, Vol. 62, pp. 183–187.

2. Custodis, F., Schirmer, S.H., Baumhäkel, M., Heusch, G., Böhm, M. and Laufs, U. (2010), “Vascular Pathophysiology in Response to Increased Heart Rate”, J. Am Coll Cardiol, pp. 56, pp. 1973–83.

3. Kannel, W.B., Kannel, C., Paffenbarger, Jr. R.S. and Cupples, L.A., (1987), “Heart Rate and Cardiovascular Mortality: The Framingham Study”, Am Heart J., Vol. 113, pp. 1489–94.

4. Diaz, A., Bourassa, M.G., Guertin, M.C. and Tardif, J.C. (2005), “Long-term Prognostic Value of Resting Heart Rate in Patients with Suspected or Proven Coronary Artery Disease”, Eur Heart J., Vol. 26, pp. 967–74.

5. Fox, K., Ford, I., Steg, P.G., Tendera, M. and Ferrari, R. (2008), Ivabradine for Patients with Stable Coronary Artery Disease and Left-ventricular Systolic Dysfunction (Beautiful): A Randomised, Double-blind, Placebo-controlled Trial”, Lancet, Vol. 372, pp. 807–16.

6. Rosendorff, C., Lackland, D.T. and Allison, M. et al. (2015), Treatment of Hypertension in Patients with Coronary Artery Disease: A Scientific Statement from the American Heart Association, American College of Cardiology and American Society of Hypertension”, J. Am Soc. Hypertens.

7. Ornish, D. et al. (1990), “Can Lifestyle Changes Reverse Heart Disease? The Lifestyle Heart Trial”, Lancet, Vol. 336, pp. 129–133.

8. Tulpule, T.H. et al. (1980), “Yoga-A Method of Relaxation for Rehabilitation after Myocardial Infarction”, Indian Heart Journal, Vol. Jan-Feb, 1980.

9. Schmidt, T., Wijga, A., Muhlen, Von Zur A., Brabant, G. and Wagner, T.O.F. (1997), “Changes in C.V. Risk Factors and Hormones during a Comprehensive Residential 3 month Kriya Yoga Training and Vegetarian Nutrition”, Acta Phys.Scand. Suppl, Vol. 161, pp. 158–162.



10. Selvanurthy, W., Sridharan, K., Ray, U.S., Tiwary, R.S., Hedges, K.S., Radhakrishnan, U. and Sinha, K.C. (1998), “A New Physiological Approach to Control Essential Hypertension”, Indian J. Physiology and Pharmacology, Vol. 42, pp. 205–213.

11. Murugesan, R., Govindrajan, N. and Bera, T.K. (2000), “Effect of Selected Yogic Practices in the Management of Hypertension”, Indian J. Physiology and Pharmacology, Vol. 44, pp. 207–210.

12. Santha, Joseph, Sridhar, K., Patel, S.K.B., Kumaria, M.L., Selvamurthy, W. and Joseph, N.T. et al. (1981), “Study of some Physiological and Biochemical Parameters in Subjects Undergoing Yoga Training”, Indian J. Medicine Res, Vol. 74, pp. 120–124.

13. Anand, B.K. (1991), “Yoga and Medical Seicences”, Indian J. Physio Pharmocol, Vol. 35(2), pp. 84–87.

14. Selvamurthy, W., Nayar, H.S., Joseph, N.T. and Joseph, S. (1983), “Physiological Effects of Yogic Practice”, Nimhans Journal, pp. 71–80.

15. Vijayalakshmi, P., Mohan, Madan, Bhavanani, A.B., Patil, Asmita and Kumar, Babu P. (2004), “Modulation of Stress Induced by Isometric Hand Grip Test in Hypertensive Patients Following Yogic Relaxation Training”, Indian J. Physiol Pharmacol, Vol. 48(1), pp. 59–60.

16. Vempati, R.P. and Telles, S. (2000), “Yoga based Guided Relaxation Reduces Sympathetic Activity Judge from Baseline Level”, Psychology Reports, Vol. 90, pp. 487–494.



Introduction

The dystonias are an unusual group of movement disorders whose main feature is involuntary muscle

contraction or spasm. The term dystonia was originally introduced by Oppenheim in 1911 to describe altering muscle tone and postural abnormalities that are seen in this condition. The dystonias represent a relatively common group of movement disorders that encompass a wide range of conditions from those where the only manifestation is dystonic muscle spasms, to those where dystonia is one part of a more severe neurological condition. Dystonia can develop at any age, although those with earlier age of onset are more likely to have a severe course affecting more of the body. We present a case of Fahr’s disease presenting as dystonia in an adolescent male. It is a rare inherited or sporadic neurological disorder with a prevalence of <1/1,000,000.

History and ExaminationA 17 year old male was admitted under us with progressive abnormal posturing of limbs during activity for past 3 years. The disease started in lower limbs as progressive difficulty in walking and difficulty in eating and handling objects since 2 years. Also he complained of difficulty in swallowing and change in voice with speech slurring since 8 months. He required assistance for walking, eating and other activities of daily living.

On examination at rest bilateral foot dystonia in the form of striatal toe was present. While speaking facial dystonia was seen. On trying to handle objects there was flexion at wrist and metacarpophalangeal joints with extension at interphalangeal joints. With medications though, patient was able to walk independently there was involuntary flexion and inversion at ankle with flexion at toes. The backward walk was much better which is characteristic of action dystonia.

InvestigationsNon contrast computed tomography (NCCT) showed calcification in bilateral basal ganglia (Fig. 1) and cerebellum. Serum calcium, phosphorous, alkaline phospahatase and parathormone were within normal limits. Skeletal survey did not reveal any sign of metabolic bone disease

Differential DiagnosisThe patient had presented with generalized, action dystonia. There was no associated parkinsonism, dementia, chorea or myoclonus. Considering pure dystonia starting in limbs and progressing cranial musculature the important etiologies would be genetic forms of pure dystonia, dopa-resposive dystonia and juvenile onset parkinsonism.[1,2] The bilateral deep calcifications along with normal blood parameters and skeletal survey established the diagnosis of Fahr’s disease.

TreatmentAs first line agent for dystonia trihexphenidyl (THP) was titrated to 30 mg/day. Tetrabenazine and gabapentin were also added. There was significant improvement as patient was able to walk and perform the activities of daily living independently.

DiscussionFahr’s disease is a rare, sporadic, condition characterized by bilateral basal ganglion calcification presenting as extrapyramidal, cognitive and psychiatric abnormalities, seizures and stroke like syndromes. It was first described by German neurologist Karl Theodor fahr’s in 1930. It can be either idiopathic or secondary to hypoparathroidism and primary neurological diseases. It is characterized by abnormal deposition of calcium in areas of the brain that control movements including basal ganglia, thalamus, dentate nucleus, cerebral cortex, cerebellum, subcortical white matter, and hippocampus. Most cases present with extra pyramidal symptoms initially. Additionally, they may present with cerebellar dysfunction, speech difficulty, dementia and neuropsychiatric symptoms. The distribution, onset and progression of dystonia in this disease are not known. In this case dystonia started in limbs

1Assistant Professor of Neurology, Department of Medicine, LLRM Medical College, Meerut, UP, India2Professor of Medicine, Department of Medicine, LLRM Medical College, Meerut, UP, India3PG Student, Dept. of Medicine, LLRM Medical College, Meerut, UP, IndiaE-mail: [email protected], [email protected]

An Unusual Cause of Generalized Dystonia Amenable to Medical Therapy

Mani Gupta1, Abha Gupta2 and Shailesh Singh3

ABSTRACTFahr’s disease is a rare entity with intracranial calcification having protean presentations. Dystonia is rare, reported in only 8% of all cases of this disease. We present a case of an adolescent male who presented with generalized action dystonia diagnosed as Fahr’s disease. There was a favorable response to medical treatment. Keywords: Dystonia, Fahr’s Disease

Original Article



progressing to cranial musculature. It was predominantly action dystonia. This profile of dystonia is quite similar to that seen in the primary pure dystonias including genetic and dopa responsive dystonia.[3] The treatment of dystonia in Fahr’s disease is not defined. Disease is as yet incurable but management and treatment strategies mainly focus on symptomatic relief and eradication of causative factors; however certain evidence is present to suggest that early diagnosis and treatment can reverse the calcification process leading to complete recovery of mental functions. There is a case report where the patient was refractory to medical treatment and responded only to deep brain stimulation.[4] However, in our case we resorted to trial of medical therapy. Apart from trihexiphenidyl and tetrabenazine at moderate dosage, the preferred drugs in dystonia, gabapentine is also useful at low dose. It has been shown that gabapentine in low doses is relieves but aggravates dystonia at high doses. It may be speculated that there is response to medical treatment, at least initially, though later only deep brain stimulation may alleviate this secondary form of dystonia.

ConclusionThis case highlights that Fahr’s disease can present

similar to primary pure dystonia, investigation as simple as NCCT can differentiate it from latter. The dystonia can be quite amenable to medical treatment and should be tried before resorting to much invasive treatment like deep brain stimulation.

References 1. Bressman, S. (2000), “Dystonia Update”, Clinical

Neuropharmacology, Vol. 23(5), pp. 239–251.2. Segawa, M. (2000), “Hereditary Progressive Dystonia with

Marked Diurnal Fluctuation”, Brain and Development, Vol. 22, pp. 65–80.

3. Nemeth, A. (2002), “The Genetics of Primary Dystonias and Related Disorder”, Brain, Vol. 125(4), pp. 695–721.

4. Ma, Y., Ge, M., Meng, F., Zhang, K. and Zhang, J. (2013), “Bilateral Deep Brain Stimulation of the Subthalamic Nucleus Effectively Relieves Dystonia Secondary to Fahr’s Disease: A Case Report”, Int J. Neurosci., Vol. 123(8), pp. 582–586.



1PG Resident of Department of Medicine, Muzaffarnagar Medical College & Hospital, Muzaffarnagar, Uttar Pradesh2Professor of Internal Medicine, Department of Medicine, Muzaffarnagar Medical College & Hospital, Muzaffarnagar, Uttar Pradesh3Department of Medicine, Muzaffarnagar Medical College and Hospital, Muzaffarnagar, Uttar PradeshE-mail: [email protected]

A Prospective Study of Outcome of Malaria— Associated Acute Kidney Injury

Harender Singh1, K.K. Pahwa2 and Ila Pahwa3

ABSTRACTMalaria remains a devastating global health problem world-wide, approximately 300–500 million people contract malaria each year, resulting in 1.5–2.7 million deaths annually. Acute kidney injury (AKI) is one of the dreaded complications of malaria. The aim of this prospective study was to determine the outcome of patients suffering from malaria with acute renal dysfunction.Material & Method: All adult patients of laboratory-proven malaria with acute kidney injury (AKI) admitted during the period of May 2014 to June 2015 were included. Patient characteristics, physical examination findings, and laboratory parameters were recorded. Patient outcome was assessed in terms of peak serum creatinine level, duration of hospital stay, need for dialysis, and in-hospital mortality rate. Surviving patients were followed up for 3 months to determine progression to chronic kidney disease.Results: This study enrolled 101 patients of malarial AKI. Mean age was 33.70 +/- 15.39 years. Oliguric AKI was observed in 44.6% cases. Mean duration of hospital stay was 8.75 +/- 7.60 days. Renal replacement therapy was required in 36.6% patients. Ten (9.9%) patients succumbed to illness during hospital stay. Majority of deaths occurred shortly after admission. Mortality risk was significantly associated with raised LDH (p = 0.019), lower hemoglobin level (p = 0.015), raised aspartate transaminases (p < 0.001), and elevated alanine transaminases (p = 0.016). Cerebral malaria was an important determinant of mortality (p = 0.002). Renal parameters, including severity of renal dysfunction and need for dialysis, were not associated with mortality risk. Among 91 survivors, 79 patients completed a 3-month follow-up and all of them had normalization of renal function.Conclusion: We observed 9.9% in-hospital mortality rate in the study cohort. Cerebral malaria was an important risk factor for mortality in malarial AKI patients. Severity of renal dysfunction did not correlate with the mortality risk in our study.Keywords: Acute Kidney Injury, Clinical Epidemiology, Complicated Malaria, Malarial AKI

Original Article

Introduction

Malaria remains a devastating global health problem world-wide, approximately 300–500 million people

contract malaria each year, resulting in 1.5–2.7 million deaths annually.[1] Acute kidney injury (AKI) is one of the dreaded complications of the malaria. The renal impairment occurs commonly in Plasmodium falciparum malaria, although, albeit less commonly, it has been reported in association with Plasmodium vivax malaria also.[2–4] Recently, there has been a changing trend not only in the clinical manifestations but also in the pattern of complications in malaria. During the last decade, cases of cerebral malaria are showing declining trend, whereas there is rapid upsurge in patients presenting with hemolysis leading to AKI.[5] Prevalence of AKI in malaria all over the world varies from 0.57 to 60%.[6–10] Such a wide variation is mainly due to differences in the criteria used todefine AKI, and characteristics of study population. Several factors, including various chemical mediators, dehydration, toxic damage to tubules due

to intravascular hemolysis and hemoglobinuria, direct toxic effect of severe hyperbilirubinemia, cytoadherence of parasitized erythrocytes, disseminated intravascular coagulation, sepsis, and hyperparasitemia leading to impaired microcirculation in peritubular capillary network, have been implicated in the pathogenesis of the renal failure in malaria.[10–15] Acute tubular necrosis is the principal pathologic mechanism in malaria-induced renal failure, whereas acute glomerulonephritis and acute interstitial nephritis are less commonly observed. This study was conducted including the patients suffering from malarial AKI, to describe the clinical characteristics, laboratory parameters and outcome of malarial AKI.

Material and MethodsThis study was conducted in the Department of Nephrology, Muzaffarnagar Medical College. Our hospital is a tertiary level referral center, located in the westernpart of Uttar Pradesh. All adult (>18 years) in-patient cases of laboratory-proven malaria with renal involvement, admitted in our nephrology unit between May 2014 and June 2015, were enrolled in the study. The study protocol was approved by local ethical committee and written informed consent was obtained from all patients. Positivity of either rapid card test or peripheral smear was considered as evidence for occurrence of malaria. Serum creatinine of 2mg/dL, persisting for more than 24h, was taken as a criterion for AKI.[3] The widely accepted RIFLE criteria were not used since baseline



serum creatinine values were not available.[16] The Acute Dialysis Quality Initiative group suggested calculating a theoretical baseline serum creatinine value using modified diet in renal diseases (MDRD) formula, assuming baseline glomerular filtration rate of 75–100mL/ min per 1.73m2 of body surface area.[17] However, the MDRD equation was validated in a large dataset of US patients with moderate chronic kidney insufficiency and it has not been validated in Indian population. Similarly, hourly urine output monitoring was also not possible in general ward. Patients were excluded from analysis if they had clinical, laboratory, and/or radiological evidence of chronicity. After the detailed history, patient were subjected to the following set of investigations: complete blood count (CBC); liver function test including total and direct bilirubin levels; aspartate transaminase (AST); alanine transaminase (ALT); and serum albumin levels, blood urea, serum creatinine, serum lactate dehydrogenase (LDH), urine analysis, and renal ultrasonography. The proven cases were treated with IV followed by oral artesunate therapy as per WHO guidelines.[18,19] Renal replacement therapy (RRT) in the form of intermittent hemodialysis was provided to patients, if required. The criteria for initiation of RRT included: presence of refractory acid–base and/or electrolyte disturbances, fluid overload, anuria for more than 24h, and presence of uremic features. Those patients with improvement were closely followed at monthly interval for 3 months, to assess recovery. On each follow-up apart from clinical examinations, the following tests were performed: CBC, blood urea, serum creatinine, and urine analysis.

Table 1: Baseline Characteristics and Laboratory Findings of Study Population (n=101)

Parameter ObservationMale/female ratio 76/25Age (years) 33.701+/-5.39P. falciparum/P. vivax/both 73/16/12Hemoglobin (g/dL) 7.844+/-2.57Platelet count (per cubic mm) (n¼97) 92,072+/-81,035Entry serum creatinine level (mg/dL) 4.09+/-2.98Peak serum creatinine (mg/dL) 4.50+/-3.04Blood urea (mg/dL) 162.88+/-81.32Serum bilirubin (mg/dL) 9.49+/-12.35ALT (IU/L) 128.53+/-352.24AST (IU/L) 179.86+/-510.51Albumin (g/dL) 2.95+/-0.57Serum LDH (IU/L) 1687.70+/-2818.867

ALT, alanine transaminase; AST, aspartate transaminase; LDH, lactate dehydrogenase.

Table 2: Outcome of Study Population of AKI Associated with Malaria

Outcome ObservationDialysis requirement 37 (36.6%)Sessions of dialysis 4.23+/-2.03Length of stay 8.75+/-7.60In-hospital mortality 10 (9.9%)

Statistical AnalysisThe statistical analysis was carried out using statistical software SPSS version 16.0 for windows. The comparison of difference in the mean values was calculated by Student’s t-test for two groups and ANOVA for more than

two groups. The difference in proportions was compared by Chi-square test of proportions. The critical value of ‘‘p’’ indicating the probability of significant difference was taken as 50.05 for comparison.

ResultsIt was a prospective study, conducted from May 2014 to June 2015. A total of 110 adult patients, suffering from malarial AKI, were admitted to our nephrology unit during this period. Among them, two patients refused to give consent, seven patients had evidence of chronic kidney disease (CKD) (bilateral shrunken kidneys on ultrasonography: four patients; diabetic nephropathy, obstructive nephropathy, and autosomal dominant polycystic kidney disease: one patient each). Rest of 101 patients was enrolled in the study. Among these 101 patient taken for the study, majority of patients were males (76, 75.2%), with a mean age of 33.7015.39 years (range: 18–75 years). Male–female ratio was 3:1. Plasmodium falciparum infection was witnessed in 73 patients, whereas infection with P. vivax and mixed infection (both P. falciparum and P. vivax) was observed in 16 and 12 patients, respectively. The baseline demographic and laboratory profile is shown in Table 1.

Regarding clinical profile, all the patients included in the study were febrile. Anemia was the second most common manifestation, seen in 70 patients (69.3%). Nearly half of the study population presented with jaundice or oligo-anuria (54.5 and 44.6%, respectively). Serum bilirubin levels of more than 10mg/dL was seen in 29 (28.3%) patients. Majority of patients presented in advanced stage of AKI. Mean levels of serum creatinine at admission and peak values were 4.092.98 and 4.503.04mg/dL, respectively, whereas seven patients had serum creatinine more than 10mg/dL during hospital stay. Twenty-two patients (21.8%) presented with cerebral malaria. Presence of hepato-and/or splenomeg- aly during ultrasonographic examination was observed in 74 (73.3%) patients. Most of the patients presented with severe hemolysis as evidenced by the presence of anemia, severe hyperbilirubinemia, increased LDH, and with only modest elevation of transaminases levels. Majority had thrombocytopenia and severe thrombocytopenia (count less than 50,000 per mm3) was seen in 44 patients (45.4%). Outcome of the study population is shown in Table 2. We observed in-hospital mortality rate of 9.9% among cases of malarial acute renal failure (ARF) and nearly one-third patients (36.6%) required RRT. Mean duration of hospital stay was 8.757.60 days. Among the remaining 91 survivors, 79 patients completed a 3-month follow-up and all of them had normalization of their hemoglobin and renal function tests at 3 months (Table 3). Significantly abnormal urine analysis was also not observed in any of these patients, after 3-month follow-up; hence, no case of persistent renal failure was observed in our study.



Table 3: Laboratory Parameters of Survivors during a 3-Month Follow-up (n=79)

Parameter Baseline First Follow-up Second Follow-up Third Follow-up p-Value (One-way ANOVA)Hemoglobin (g/dL) 8.09+/-3.07 10.33+/-1.92 11.79+/-1.57 12.82+/-1.19 <0.001Serum creatinine (mg/dL) 4.46+/-3.00 1.16+/-0.34 0.99+/-0.16 0.98+/-0.16 <0.001Blood urea (mg/dL) 159.68+/-81.15 27.04+/-10.62 21.06+/-7.68 18.51+/-7.56 <0.001

Table 4: Comparison of Patient Characteristics and Laboratory Parameters between Mortality and Survivor Groups

Parameters Expired (n = 10) Improved (n = 91) t-Value p-ValueAge 36.71+/-5.49 33.43+/-13.87 0.699 0.486Sex(male) 6(60%) 70(76.92% 0.258Cerebral malaria 6 (60) 16(17.6) 0.002*Oligo-anuria 5(50%) 40(43.96%) 0.748Dialysis requirement 6(60%) 31(34.06%) 0.171Duration of stay (days) 3.70+/-2.26 9.30+/-8.39 2.093 0.039*Hemoglobin (g/dL) 5.34+/-4.52 8.12+/-3.24 2.471 0.015*Platelet count 72,200.00+/-96,121.22 94,356.32+/-79,448.97 0.817 0.416Serum creatinine at admission (mg/dL) 3.96+/-1.78 4.10+/-2.57 0.167 0.868Peak serum creatinine (mg/dL) 4.26+/-2.51 4.53+/-3.10 0.263 0.793Blood urea (mg/dL) 177.80+/-87.87 161.24+/-80.92 0.609 0.544ALT (IU/L) 380.20+/-716.30 100.57+/-279.69 2.440 0.016*AST (IU/L) 734.40+/-1541.06 118.24+/-106.56 3.868 <0.001*Serum LDH (IU/L) 4203.67+/-6926.39 1385.78+/-1776.36 2.413 0.019*

*Values are statistically significant.

Correlation with Mortality RiskCharacteristics of 10 patients, who died, were compared with the remaining 91 patients to determine the factors associated with increased risk of mortality (Table 4). There were no statistically significant differences in terms of age and gender. The mortality was significantly higher in the patients having cerebral malaria (p=0.002). Total 37 patients were dialyzed, out of which 36 patients had shown improvement and 1 patient expired (p=0.171). Similarly, there were no statistically significant differences in terms of entry serum creatinine or peak serum creatinine levels (p=0.868 and 0.793, respectively). Hence, severity of renal dysfunction or dialysis requirement was not a predictor of mortality in our study. Mortality was significantly higher among the patients having raised serum LDH (p=0.019), anemia (p=0.015), suggestive of intravascular hemolysis, and in the patients having raised AST and ALT levels (p<0.001 and 0.016, respectively).

DiscussionMalaria is a common and serious health problem in India and has considerable morbidity and mortality. In India, the reported incidence of malarial AKI ranges from 13 to 17.8% of all AKI cases, in various geographical regions. 20 Malarial AKI in Indian patients carries high mortality whichvaries from 11.9% to 29%. 3,10,21,22 This study was carried out in patients having complicated malaria with acute renal dysfunction, in an Indian setting. In our prospective study, we intended to assess demographic profile and outcome of malarial AKI. In our study, 75% cases were between 18 and 40 years of age group, though it involved all the age groups. The male sex group showed a higher incidence (3:1) than the female sex group. In endemic areas such as India, younger population, especially males, are at high risk of being affected, probably due to their outdoor occupation and hence proximity to vector contact. The results were in no- way dissimilar to other studies.[6,18]

Anemia was present in 69% patients, which was severe in most of the patients. Anemia in malaria is due to hemolysis of parasitized RBCs, splenic hyperactivity, and/or bone marrow suppression. Raised bilirubin levels in association with elevated serum LDH, anemia, and modest increase in transaminase levels are suggestive of hemolysis. Severe intravascular hemolysis manifesting as triad of anemia, jaundice, and renal failure, is the most characteristic feature of malarial AKI. In fact, presence of this triad leads to suspicion of malaria, in majority of the cases of febrile illness. However, presence of very severe hyperbilirubinemia in malaria indicates the possibility of intra-hepatic cholestasis.[23] Both conjugated and unconjugated bilirubin have been shown to be involved in the pathogenesis of acute renal failure in P. falciparum malaria.[24,25] In a previous study by Prakash et al., severe jaundice (serum bilirubin: 11.8–23.4mg/dL) was observed in six (23%) patients, with biochemical evidence of cholestasis in all of them.[26] Cerebral symptoms were observed in 21.8% patients, similar observations have docu- mented in past studies also.[3,18,27]

AKI in malaria is usually oliguric and hypercatabolic, which may last for days to weeks.[18] Oligo-anuric AKI was the presentation in 44.5% of our cases, which is lower than 60–70% proportion of oliguric ARF reported in other studies.[6,18,26] Our speculation behind this lower incidence is that our study included only patients directly admitted in nephrology unit, which can handle fluid and electrolyte disturbances in more efficient manner, whereas, in other studies, patients referred from other medical and surgical units were also included. We observed 9.9% in-hospital mortality in our cohort of malarial ARF cases which is lower than from other studies reported from Indian subcontinent.[3,6,18,21,22] Majority of deaths occurred within first 48h after admission and mean duration of hospital stay was shorter in patients who died (p = 0.039). Prolonged duration of illness, before reaching the dialysis facility, severity of AKI, and/or multi-organ involvement probably explains these early deaths in our



patients. Similar observations were reported in a study from Thailand, where 58.3% patients died during the first 24h after admission.[28] Concomitant presence of cerebral malaria was noted in 22 patients, out of which 6 patients died. Thus, the presence of cerebral malaria significantly predicted adverse outcome (p = 0.002). Association of cerebral malaria with mortality have been reported previously also.[6,18,26] Raised LDH levels (p = 0.019) and lower hemoglobin levels (p = 0.015) significantly predicted mortality. Similarly, elevated AST (p < 0.001) and ALT (p = 0.016) were significantly associated with mortality risk in our study. In human body, AST has multiple sources of origin, including liver, RBCs, and muscle cells. Very high levels seen in our study were probably because of hemolysis of RBCs. ALT is considered as better marker of acute liver injury, and its association with increased risk of death have been reported previously also.18 Mortality risk in our study was not associated with the presence of oliguric AKI, severity of renal dysfunction, leukocytosis, thrombocytopenia, and presence and severity of jaundice. Similarly, mortality was not significantly higher in patients requiring dialysis (p = 0.171). It seems that severity of renal dysfunction is not a sole determinant of poor outcome in patients with malarial AKI, and majority of deaths in malarial AKI are preventable, provided patient receives specialized care early during disease course. However, degree of renal dysfunction has been found to be a risk factor for mortality in few studies.[18,22]

Surviving patients were followed-up for 3 months, to assess recovery of renal function. Normalization of renal function was noted in all of the patients who completed follow-up. Hence, it can be concluded that malarial AKI is reversible and does not affect the long-term renal prognosis. In contrast, a retrospective study reported that 15% of their patients had partial recovery or dialysis dependency, however, whether this was recorded at time of discharge or during follow-up was not mentioned.[22]

Our study had few distinctive features. First, our study enrolled patients from nephrology unit only, and reported lower proportion of oliguric AKI and mortality rate than from other studies reported from Indian subcontinent, with similar background. Second, severity of renal dysfunction and need for dialysis were not predictor of mortality. Hence with early referral and, efficient and timely RRT, majority of malarial AKI cases can be salvaged. Third, we followed-up patients for 3 months to determine progression to CKD.

Available literature (from this region) described partial recovery or non-recovery at time of discharge only, which is not a sensitive parameter. In summary, this prospective study examined patient characteristics of 101 cases with malarial ARF, admitted during 1 year study period, to assess patient outcome, and followed-up them for 3 months. Nearly 37% patients required dialysis. Our study witnessed in-hospital mortality rate of 9.9% among cases of malarial AKI and majority of patients succumbed

shortly after admission. Mortality risk was higher in patients having cerebral malaria, severe hemolysis as evident by raised LDH, elevated AST and ALT, and lower hemoglobin levels. Severity of renal dysfunction and dialysis requirement did not predicted mortality risk. Our study highlights the fact that availability of timely dialysis therapy may improve outcome in these patients.

Declaration of InterestThe authors report no conflicts of interest. The authors

alone are responsible for the content and writing of the paper.

References1. Malaria, Osler W., Fauci, A.S., Braunwald, E. and Kasper,

D.L. et al., eds. (2008), Harrison’s Principles of Internal Medicine, 17th ed. New York: McGraw-Hill, pp. 1280–1294.

2. Barsoum, R.S. and Sitprija, V., Tropical Nephrology, In: Schrier, R.W. and Gottaschalk, C.W., eds. (1996), Diseases of the Kidney, VI ed. Boston, MA: Little Brown & Co., pp. 2221–2268.

3. Prakash, J., Singh, A.K., Kumar, N.S., Saxena, R.K. (2003), “Acute Renal Failure in Plasmodium Vivax Malaria”, J. Assoc. Phys. India, Vol. 51, pp. 265–267.

4. Trampuz, A., Jereb, M., Muzlovic, I. and Prabhu, R.M. (2003), “Clinical Review: Severe Malaria”, Crit Care, Vol. 7, pp. 315–323.

5. Nand, N., Aggarwal, H.K., Sharma, M. and Singh, M. (2001), “Systemic Manifestations of Malaria”, J. Indian Acad. Clin. Med., Vol. 2, pp. 189–194.

6. Naqvi, R., Ahmad, E. and Akhtar, F. et al. (2003), “Outcome in Severe Acute Renal Failure Associated with Malaria”, Nephrol Dial Transplant, Vol. 18, pp. 1820–1823.

7. Boonpucknavig, V. and Sitprija, V. (1979), “Renal Disease in Acute Plasmodium Falciparum Infection in Man”, Kidney Int., Vol. 16, pp. 44–52.

8. Singh, N., Shukla, M.M. and Sharma, V.P. (1999), “Epidemiology of Malaria in Pregnancy in Central India”, Bull World Health Organ., Vol. 77, pp. 567–572.

9. Sheehy, T.W. and Reba, P.C. (1967), “Complications of Falciparum Malaria and their Treatment”, Ann Inter Med., Vol. 66, pp. 807–809.

10. Mehta, K.S., Halankar, A.R., Makwana, P.D., Torane, P.P., Satija, P.S. and Shah, V.B. (2001), “Severe Acute Renal Failure in Malaria”, J. Postgrad Med., Vol. 47, pp. 24–26.

11. Eiam-Ong, S. and Sitprija, V. (1998), “Falciparum Malaria and the Kidney: A Model of Inflammation”, Am J. Kidney Dis., Vol. 32, pp. 361–375.

12. Dvorak, J.A., Miller, L.H., Whitehourse, W.C. and Shiroishi, T. (1975), “Invasion of Erythrocytes by Malaria Merozoites”, Science, Vol. 187, pp. 748–750.

13. Borochovitz, D., Crosley, A.L. and Metz, J. (1970), “Disseminated Intravascular Coagulation with Fatal Hemorrhage in Cerebral Malaria”, Br. Med. J. (Clin Res)., Vol. 2, p. 710.



14. Devakul, K., Harinsuta, T. and Reid, H.A. (1966), “125I Labelled Fibrinogen in Cerebral Malaria”, Lancet, Vol. 2, pp. 886–888.

15. Srichaikul, T., Puwasatien, P., Karnjanajetanee, J. and Bokisch, V.A. (1975), “Complement Changes and Disseminated Intravascular Coagulation in P. Falciparum Malaria”, Lancet, Vol. 1, pp. 770–772.

16. Bellomo, R., Ronco, C., Kellum, J.A., Mehta, R. and Palevsky, P. (2004), “The ADQI Workgroup. Acute Renal Failure–Definition, Outcome Measures, Animal Models, Fluid Therapy and Information Technology Needs: The Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group”, Crit Care, Vol. 8, pp. R204–R212.

17. Levey, A.S., Bosch, J.P., Lewis, J.B., Greene, T., Rogers, N. and Roth, D. (1999), “A More Accurate Method to Estimate Glomerular Filtration Rate from Serum Creatinine: A New Prediction Equation, Modification of Diet in Renal Disease Study Group”, Ann Intern Med., Vol. 130, pp. 461–470.

18. Manan, J.A., Ali, H. and Lal, M. (2006), “Acute Renal Failure Associated with Malaria”, J. Ayub. Med. Coll. Abbottabad, Vol. 18, pp. 47–52.

19. World Health Organization: Guidelines for the Treatment of Malaria, Geneva, World Health Organization, 2006. Available at: http:// www.who.int/malaria/docs/ProtocolWHO.pdf. Accessed June 6, 2012.

20. Sharma, A.K., Arora, M., Gupta, H. and Gupta, R. (1998), “Malarial Acute Renal Failure in Rajasthan”, J. Assoc. Phys. India, Vol. 46, pp. 1001–1002.

21. Kute, V.B., Shah, P.R. and Munjappa, B.C. et al. (2012), “Outcome and Prognostic Factors of Malaria-associated Acute Kidney Injury Requiring Hemo-dialysis: A Single Center Experience”, Indian J. Nephrol, Vol. 22, pp. 33–38.

22. Kanodia, K.V., Shah, P.R., Vanikar, A.V., Kasat, P., Gumber, M. and Trivedi, H.L. (2010), “Malaria Induced Acute Renal Failure: A Single Center Experience”, Saudi J. Kidney Dis. Transplant, Vol. 21, pp. 1088–1091.

23. Dash, S.C., Bhuyan, U.N., Gupta, A., Sharma, L.C., Kumar, A. and Agarwal, S.K. (1994), “Falciparum Malaria Complicating Cholestatic Jaundice and Acute Renal Failure”, J. Assoc. Phys. India, Vol. 42, pp. 101–102.

24. Baum, M., Sterling, G.A. and Dawson, J.L. (1969), “Further Study into Obstructive Jaundice and Ischemic Renal Damage”, Br. Med. J., Vol. 2, pp. 229–232.

25. Aoyagi, T. and Lowenstem, L.M. (1969), “The Effect of Bile Acid and Renal Ischemia on Renal Function”, J. Lab. Clin. Med., Vol. 71, pp. 686–690.

26. Prakash, J., Gupta, A., Kumar, O., Rout, S.B., Malhotra, V. and Srivastava, P.K. (1996), “Acute Renal Failure in Falciparum Malaria: Increasing Prevalence in Some Areas of India–A need for Awareness”, Nephrol Dial Transplant, Vol. 11, pp. 2414–2416.

27. Habte, B. (1990), “Acute Renal Failure Due to Falciparum Malaria”, Renal Fail, Vol. 12, pp. 15–19.

28. Wilairatana, P., Westerlund, E.K. and Aursudkij, B. et al. (1999), “Treatment of Malarial Acute Renal Failure by Hemodialysis”, Am J. Trop. Med. Hyg., Vol. 60, pp. 233–237.



1PG Resident of Department of Internal Medicine, Muzaffarnagar Medical College & Hospital, Muzaffarnagar, Uttar Pradesh2Professor, Internal Medicine, Department of Medicine, Muzaffarnagar Medical College & Hospital, Muzaffarnagar, Uttar Pradesh3Department of Medicine, Muzaffarnagar Medical College & Hospital, Muzaffarnagar, Uttar PradeshE-mail: [email protected]

Anti-Inflammatory Effect of Statins in Chronic Obstructive Pulmonary Disease

Shalini Sharma1*, Ila Pahwa2 and Jayant Mudgal3

ABSTRACTStatins are now becoming recognized as powerful anti-inflammatory agents that exert beneficial effects beyond low-density lipoprotein cholesterol reduction 1. COPD patients receiving statins obtain a benefit from these therapeutic agents. Clearly, the best medical evidence for the association of statins with improved outcomes for COPD patients 2. We aimed in this study to assess anti inflammatory effects of statin in COPD patients.Material & Method: The study comprises of 114 patients of COPD who fulfills inclusion criteria’s and after excluding exclusion criteria’s. Patients divided in three groups, first ‘A’ group of 42 patients, second ‘B’ group of 37 patients and ‘C’ group of 35 patients as control. Group ‘A’ and ‘B’ has given 40,80 mg./day Atorvastatin drug respectively for 6 month duration along with standard treatment of COPD as given only to group ‘C’ patients. Each patient is subjected to 3 sequential pulmonary function test at 0, 3rd and 6th month of treatment duration.Results: There is significant improvement in pulmonary functions in both the groups ‘A’ and ‘B’ but group C showed significant decline in FEV1 at both 3rd and 6th month.Conclusion: Statins can be used as an adjuvent therapy in COPD patients because of its anti inflammatory properties. It not only results in gradual improvement in FEV1 of such patient but also reduces the number of acute of exacerbation episodes.Keywords: Chronic Obstructive Pulmonary Disease, Forced Expiratory Volume, Statins

Original Article

Introduction

COPD is the fourth leading cause of death in the world and further increases in its prevalence and mortality

can be predicted in the coming decades.[3] By the year 2020, COPD is expected to be the third leading cause of death and the fifth leading cause of disability.[4] COPD has been defined by the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) an international collaborative effort to improve awareness and diagnosis and treatment of COPD, as a disease state characterized by airflow limitation that is not fully reversible.

Cigarette smoking is the most important risk factor leading to the development of COPD. Smoking accounts for nearly 90% cases of COPD. COPD is the major cause of mortality and morbidity in India. Other risk factors for COPD are mainly recurrent respiratory infection, occupational exposures, ambient air pollution and passive or second hand smoking exposure like exposure of children to maternal smoking results in significantly reduced lung growth.

Statins, 3 hydroxy-3-methyl-glutarylcoenzyme–A (HMG–CoA) reductase inhibitors, are widely used in the treatment of patients with hypercholesterolemia. They are considered first line therapy for coronary

artery disease and stroke due to their known efficacy in improving lipid profiles and their direct vascular actions. Although the benefits of statins are primarily attributed to their lipid lowering effects, accumulating evidence suggests the possibility of effects independent from their effect on serum cholesterol levels.[5,6,7] These effects are thought to be related to their anti inflammatory, antioxidant, antithrombogenic, and vascular function restoring actions. Interestingly, all of these additional actions may counteract some of the harmful effects of cigarette smoking induced chronic inflammation.

In present study, we have evaluated the possible beneficial effect of statins on the lung functions, in different group of patients of COPD diseases.

Material & MethodThe present study was undertaken in Department of Medicine of Muzaffarnagar Medical College and Hospital, Muzaffarnagar. The study comprises of 114 patients of COPD who fulfils inclusion criteria and after excluding exclusion criteria. Patients divided in three groups, first ‘A’ group of 42 patients, second ‘B’ group of 37 patients and ‘C’ group of 35 patients as control. Group ‘A’ and ‘B’ has given 40,80 mg/day Atorvastatin drug respectively for 6 month duration along with standard treatment of COPD as given only to group ‘C’ patients. Each patient is subjected to 3 sequential pulmonary function test at 0,3rd and 6th month of treatment duration.

Inclusion Criteria includes Patients of age group between 40 to 60 years with informed and written consent having chronic history of smoking and fulfilling GOLD criteria of COPD with stage 1, 2 & 3 (GOLD classification)

Exclusion Criteria includes Age less than 40 and without history of significant smoking and Any Patient



not fulfilling GOLD criteria and of stage 4 COPD disease (GOLD criteria) Patients having elements of hypertension, coronary artery disease, pulmonary tuberculosis, diabetes mellitus should be excluded.and patients having contraindication of PFT recent MI, active bleeding,respiratory distress.

Every patient was subjected to Routine examination (Haemogram, ESR, Blood Sugar,and Blood urea) and Sputum examination for AFB staining–(atleast two samples), Chest X-Ray followed by Pulmonary Function test three times (at 0, 3rd, 6th month ) and any Other investigations like ECG, Fasting lipid profile, 2D-ECHO if required. Each patient was followed up monthly upto six months. During the study each patient was subjected to 3 PFTs serially at start of treatment (baseline), 3rd and lastly at the end of 6 month of study.

The result were calculated by using appropriate statistical tests. To compare the difference in the response of drug, the FEV1 at the end of the study for both the group A and B were compared using unpaired student ‘T’ test.

ResultIn the present study, data of 114 COPD patients was assessed, Group A included 42 patients, Group B included 37 patients and Group C included 35 patients.

Patient in group A were given 40mg atorvastatin daily for 6 month along with standard treatment of COPD. Mean FEV1 at baseline was 55.88 ± 12.63% and 56.69 ± 12.73% at 3rd and 6th month respectively. Improvement FEV1 from baseline was not statistically significant at 3rd month (p = 0.107) whereas there was significant improvement in FEV1 from the baseline at the end of 6 month (p < 0.0001).From the observation above it was concluded that patients in group A showed significant improvement in FEV1 at 6 months with 40 mg of atorvastatin. (As shown in Table 1)

Table 1: Mean FEV1 at Baseline & during Follow up in Group A

S. No. Month Mean FEV11 a

1 Baseline 55.88±12.63%2 3rd month 56.69±12.79%3 6 th month 58.47±12.73%

aAbbreviations: FEV, Forced expiratory volume

Patient in group B were given 80 mg atorvastatin daily for 6 month along with standard treatment of COPD. Mean FEV1 at baseline was 53.24 ± 8.78% and 54.72 ± 8.84%, 55.94 ± 8.79% at 3rd and 6th month respectively. Improvement in FEV1 from baseline was significant at 3rd month (p = 0.0001) and 6 month (p < 0.0001). From this we concluded that patient in group B showed significant improvement in FEV1 at both 3rd and 6th months with 80 mg of atorvastatin. (As shown in Table 2).

Table 2: Mean FEV1 at Baseline and During Follow up in Group B

S. No. Month Mean FEV1b

1 Baseline 53.24±8.78% 2 3rd month 54.72±8.84% 3 6th month 55.94±8.79%

bAbbreviations: FEV, Forced expiratory volume

Patient in group C were treated with standard treatment of COPD. During follow up patient showed significant decline in FEV1 at 3rd month (p = 0.042) and 6th month (p = 0.0109). From the observation it was concluded that patient in group C showed significant decline in FEV1 at both 3rd and 6th month (as shown in Table 3)

Table 3: Mean FEV1 at Baseline and During Follow up in Group C

S. No Month Mean FEV1c

1 Baseline 58.23±13.75% 2 3rd month 55.71±14.70% 3 6th month 53.71±15.61%

cAbbreviations: FEV, Forced expiratory volume.

It was concluded from the comparison between the groups that mean FEV1 during follow up (at 3rd and 6th month) showed increasing trend (improvement in lung function) in group A and B whereas decreasing trend (decline in lung function) was seen in group C. (as shown in Table 4).

Table 4: Comparison of Mean FEV1 at Baseline and during Followup between Different Groups

S. No. Group FEV1 (baseline)

FEV1 (3rd Month)

FEV1 (6th Month)

1 A 55.88±12.63% 56.69±12.79% 58.47±12.73%2 B 53.24±8.78% 54.72±8.84% 55.94±8.79%3 C 58.23±13.75% 55.71±14.70% 53.71±15.61%As shown in Table 5 patients in group A and B

had lesser episodes of acute exacerbation compared to patients in group C. On comparing group A with B patients in group B showed lesser number of episodes of acute exacerbation compared to group A.

Table 5: Number of Episodes of Acute Exacerbation in Patients of different Groups

S. No. Group No of Patient No. of Episodes of Ac.exacerb

Episodes Per Patient Per Year

1 A 42 9 0.428 2 B 37 5 0.270 3 C 35 13 0.742

DiscussionChronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of death and is also a disease of increasing public health importance around the world. Global initiative for Chronic Obstructive Pulmonary Disease (GOLD) estimates suggest that COPD will rise from the sixth to third most common cause of death worldwide by 2020.[8]

The 3–hydroxy-3 methylglutaryl coenzyme A reductase inhibitors (ie statins) are widely used for the treatment of patients with hypercholesterolemia and cardiovascular disease. Emerging evidence suggests a beneficial effect of statins on the morbidity and mortality of patients with COPD.

The FEV1 is essential for diagnosis and quantification of respiratory impairment resulting from COPD. In addition rate of decline in FEV1 is a good marker of disease progression and mortality.

In our study, the Patients were adviced to take 40 mg and 80 mg of atorvastatin along with standard treatment



of COPD in group A(n = 42) & B(n = 37) respectively and only standard treatment of COPD to group C (control group, n=35). FEV1 at baseline and during follow up at 3rd and 6th month were recorded for each patient and then values were compared within each group at baseline, 3rd and 6th month. We noted that there was significant improvement in FEV1 in 3rd and 6th month in Group A and Group B as compared to Group C.

Nine studies were identified for review (four retrospective cohorts, one nested case control study of a retrospective cohort, one retrospective cohort and case series, two population based analyses and one RCT). All studies showed a benefit from statin therapy for various outcomes in COPD patients,including the number of COPD exacerbations (n = 3), pulmonary functions (FEV1)(n = 1), mortality from COPD (n = 2).

In a similar study Jean I. Keddissi et al.[9] in 2005, all smokers with abnormal baseline spirometry and two or more Pulmonary function test done 6 month apart were compared.

Approximately half, 215 of 418 patients, were on a statin. Compared to the control group, statin users had a lower decline in FEV1 (-0.005+/-0.20 vs. 0.085+/-0.17 L/y, p < 0.0001) and FVC (-0.046+/-0.45 vs. 0.135+/-0.32 L/y, p < 0.0001). This difference remained significant irrespective of whether the patient had obstructive (n = 319), or restrictive (n=99) disease used, annual decline in FEV1 ( P < 0.0001) and FVC (p < 0.0001).

In a study conducted by Nasef Abdelsalam rezk et al.[10] 2012, in this study no difference between two groups regarding age,pulmonary function and exacerbation ten month before introduction of statins were found. But after 10 month of statin use there was a significant improvement in FEV1 and exaberation in statin group as compared to control group.

ConclusionThe beneficial effects of statins are seen irrespective.

Atorvastatin can be used as adjuvant therapy in COPD patients because of its anti inflammatory properties.It not only results in gradual improvement in FEV1 of such patients but also reduces the number of acute of exacerbation episodes.

More studies, with larger number of cases and larger number of controls, would possibly shed more light on the definite role of atorvastatin in chronic obstructive pulmonary disease.

AcknowledgementWe thank Dr. Kanchan Singh for her valuable help in preparing this manuscript.

References1. Pruefer, D., Makowski, J. and Schnell, M. et al. (2002),

“Simvastatin Inhibits Inflammatory Properties of Staphylococcus Aureus Toxin”, Circulation, Vol. 106, pp. 2104–2110.

2. Armitage, J. (2007), “The Safety of Statins in Clinical Practice”, Lancet, Vol. 370, pp. 1781–1790.

3. Lopez, A.D., Shibuya, K., Rao, C., Hoters, C.D., Hansell, A.L., Held, L.S. et al. (2006), “Chronic Obstructive Pulmonary Disease Current Burden and Future Projections”, European J., Vol. 27(2), pp. 397–412.

4. Murray, C.J. and Lopez, A.D. (1997), “Alternative Projection of Mortality by Cause 1990–2020: Global Burden of Disease Study”, Lancet, Vol. 349, pp. 1498–504.

5. Munford, R.S. (2001), “Statins and the Acute-Phase Response”, N. Engl. J. Med., Vol. 344, pp. 2016–2018.

6. Sparrow, C.P., Burton, C.A., Hernandez, M. et al. “Simvastatin Hasanti-inflammatory and Antiatherosclerotic Activities Independent of Plasma Cholesterol Lowering”, Arterioscler Thromb Vasc Biol., 2001 Jan., Vol. 21(1), pp. 115–21.

7. Weitz-Schmidt, G. (2002), “Statins as Anti-inflammatory Agents”, Trends Pharmacol Sci., 2002 Oct., Vol. 23(10), pp. 482–86.

8. Reilly, John J. and Silverman, Edwin K. (2008), “Chronic ObstructivePulmonary Disease in : Harrison’s Principles of Internal Medicine”, Anthony S. Fauci and Eugene Braunwald (eds). McGraw-Hill Companies, USA, 17th

Edition, Vol. 2, pp. 1635–1636.9. Keddissi, Jean I., MD, FCCP, Younis, Walid G. , MD;

Chbeir, Elie A. et al. (2007), “The Use of Statins and Lung Function in Current and Former Smokers”, Chest, Vol. 132, pp. 1764-1771.

10. Rezk, Nasef Abdelsalam and Elewa, Ahmad et al. (2013), “Anti Inflammatory Effects of Statin in COPD”, Egyptian Journal of Chest Diseases and Tuberculosis, Vol. 62, pp. 65–69.



Introduction

For any motor activity three basic things are needed:• Initiation of movement• Continuation of movement• Co-ordination of movementThis is achieved by Extra-pyramidal, Pyramidal

system and cerebellum.[1] The job of cerebellum is Co-ordination of motor activities.

Anatomy & PhysiologyCerebellum (latin: little brain) is a part of hindbrain situated in posterior cranial fossa, behind medulla oblongata and pons and separated from the same by 4th ventricle .It is covered by tentorium cerebelli.It is connected to the midbrain by superior cerebellar peduncle,to the pons by the middle cerebellar peduncle and by the inferior cerebellar peduncle to the medulla.In adults is weighs roughly one tenth of the cerebrum.The central part is known as vermis and is flanked by the lateral hemispheres. The surface is divided by numerous curves giving it a laminated appearance.[1] The cerebellum is divided into three main lobes: the anterior lobe, the posterior lobe, and the flocculonodular lobe.

Functional Subdivisions and Relevant EmbryologyBy this way cerebellum is connected to same side proprioceptice sensations & vestibule and to opposite side cerebral cortex & red nucleus.

Table 1: Functional Subdivisions and Relevant Embryology

Embryological Denomination

Relevant Anatomy Functions

Archicerebellum (aka vestibulocerebellum)

Flocculonodular Lobe and nearby Vermis

Concerned ith equilibrium,balance and eye movements.

Paleocerebellum (aka spinocerebellum)

Vermis and adjacent hemispheres (except nodulus and subdivision VII)

Regulates body and limb movements like walking

Neocerebellum (aka pontocerebellum, cerebrocerebellum)

Lateral Parts of Hemispheres

Planning movement and evaluating sensory information for action. It also displays cognitive functions

Nucleus and Connections

Table 2: Nucleus and Connections

Nuclei Connections RoleDentate (largest of all nuclei, shaped like a crumpled bag, forms part of neocerebellum)

dentate → opposite ventrolateral nucleus of thalamus → opposite cerebral cortex → corticospinal tract

Dorsal region-responsible for the planning, initiation and control of voluntary movements. Ventral–cognitive and visuospatial function

Emboliform-Globose Nucleus (forms part of spinocerebellum, collectively known as interposed nuclei)

Interposed Nuclei→Opposite Red Nucleus→Crossed Rubrospinal Tract

The pathway crosses twice so influences ipsilateral motor activity

Fastigial Nucleus (forms part of vestibulocerebellum)

1. Fastigial nucleus→bilateral vestibular nucleus [ICP]; lateral vestibular nuclei→ vestibulospinal tract

2. Fastigial nucleus→reticular formation→reticulospinal tract

1. Fastigial vestibular -Provides facilitatory influence mainly on the ipsilateral extensor muscle tone

2. Fastigial reticular- influences ipsilateral muscle tone

Four masses of gray matter are embedded in the white matter of the cerebellum on each side of the midline . From lateral to medial, these nuclei are the dentate, the emboliform, the globose, and the fastigial

1,2Assistant Professor, Department of Medicine, JN Medical College, AMU, Aligarh–202002, UP, India 3Professor and Chairman, Department of Medicine, JN Medical College, AMU, Aligarh–202002, UP, India

Acute Cerebellar AtaxiaDr. Anjum Mirza Chughtai1, Dr. Muhammad Uwais Ashraf2 and Prof. M.R. Ajmal3

ABSTRACT

Cerebellum (latin: little brain) is a part of hindbrain situated in posterior cranial fossa, behind medulla oblongata and pons and separated from the same by 4th ventricle. The cerebellum is divided into three main lobes: the anterior lobe, the posterior lobe, and the flocculonodular lobe. Degenerative diseases, developmental defects and endocrinal diseases like myxedema, hypoparathyroidism can cause cerebellar ataxia (usually slow, subacute to chronic). Adults with large unilateral or bilateral cerebellar lesions that involve the posterior lobe manifest a constellation of cognitive, affective and behavioral abnormalities that are clinically relevant and detectable on bedside mental state tests. Deficient executive functions include working memory, motor or ideational set shifting, and perseveration of actions or drawings; and impairment of verbal fluency that manifests as telegraphic speech. We present here a systematic overview of Acute manifestations of Cerebellar ataxia in an attempt to revisit the literature which is exhaustive.

Review Article



The cerebellum is connected to Brain stem by three peduncles Superior cerebellar peduncle

Middle cerebellar peduncle

Inferior cerebellar peduncle

Functional Zones

VESTIBULOCEREBELLUM (BALANCE & EYE MOVEMENT)

CEREBROCEREBELLUM (PLANNED MOVEMENT, MOTOR LEARNING, COGNITIVE FUNCTIONS)

SPINOCEREBELLUM(BODY AND LIMB MOVEMENT)

Functional(Evolutionary)

Paleocerebellum

Neocerebellum

Archicerebellum Pons



Middle cerebellar peduncle

Inferior cerebellar peduncle

Functional (Evolutionary)

SPINOCEREBELLUM (BODY AND LIMB MOVEMENT)

CEREBROCEREBELLUM(PLANNED MOVEMENT,MOTOR LEARNING,COGNITIVE FUNCTIONS)

VESTIBULOCEREBELLUM(BALANCE & EYE MOVEMENT)

Functional Zones

Paleocerebellum

Neocerebellum

Archicerebellum

Primary fissure

Superior vermis

Anterior lobeHemisphere

Posterior lobe

Interior vermis

Hemispere

Primary FissureAnterior Lobe

Posterior Lobe

Flocculus

Nodulus

Horizontal Fissure

Posterior Fissure

Flocculonodular Lobe

Vermis

Pons

Nodule

Flocculonodular lobe

Flocculus

Horizontal fissure

Posterolateral fissure

Superior peduncle

Acoustic nervePyramid

Olive

Trigeminal nerve

Inferior peduncle

Inferior peduncle

Middle peduncle

Tracts and PedunclesPeduncles Afferents Efferents

Superior Cerebellar Peduncle

1. Ventral Spinocerebellar Tract (proprioception from upper limb and lower limb)

2. Tectocerebellar Tract (auditory and visual impulse via relay in inferior and superior colliculi)

1. Globose-Emboliform Rubral Pathway (influence ipsilateral motor activity)

2. Entatothalamic Tract (circuitry shows double crossing at so influence ipsilateral motor activity)

Middle Cerebellar Peduncle Fibres from motor cortex and other parts of frontal,parietal,temporal and occipital cerebellar hemisphere via a relay in pontine nuclei cross midline to enter contralateral cerebellar cortex

Inferior Cerebellar Peduncle 1. Dorsalspino Cerebellar Tract (proprioception from trunk and lower limb)

2. Cuneocerebellar Tract (proprioception from head and neck)3. Vestibulocerebellar Tract (vestibular impulse from labyrinths directly

and via vestibular nuclei)4. Olivocerebwellar Tract (motor learning & specialized motor

tasks;internal arcuate fibres form the deeper and larger part of ICP)

1. Fastigial Vestibular Tract (ipsilateral extensor muscle tone)

2. Fastigial Reticular Tract (ipsilateral muscle tone)



Causes of Acute Cerebellar Ataxia1. Acute Infections: May produce only cerebellitis or

form a part of meningoencephalitis . eg, coxsackie virus, HIV, EB virus, Chickenpox causing virus. Borrelia burgdoferi, mycoplasma.[2]

2. Vascular: Acute cerebellar haemorrhage is one of the rare emergency which presents as sudden severe headache and unconsciousness. May be fatal. Neurosurgical intervention is lifesaving.Cerebellar infarctTIA of posterior circulation

3. Cerebellar Abscess4. Injury5. Toxins: Pesticides ,alcohol,mercury ,drugs,etc.

alcohol classicaly damages the vermis. Chronic alcoholics due to loss of self care and reduced motility may be diagnosed as suffering from depression

6. Demyelinating Diseases: Multiple Sclerosis and other demyelination conditions may present as acute cerebellar ataxia [3]

7. Neoplastic: Medulloblastomain children & posterior fossa tumor in adults can manifest as cerebellar ataxia

8. Vaccination9. Raised ICT: Any abnormalty causing increased

intracranial tension may cause tonsillar herniation (usually fatal unless intervened)

Degenerative Diseases, Developmental Defects and Endocrinal Diseases Like Myxedema, Hypoparathyroidism can cause Cerebellar Ataxia (usually slow, subacute to chronic)

Symptomatology1. Gait Difficulties2. Headache3. Nausea/Vomiting4. Dizziness5. Clumsiness in Hands6. Speech Difficulties7. Tremor8. Blurred Vision9. Diplopia10. Feebleness11. Sensory Complaints12. Memory Difficulties13. Impotence14. Swallowing Difficulties

15. Hearing Loss16. Limb/Facial Weakness17. Cognitive and Emotional SymptomsFive general principles apply:[5]

1. Lateral focal cerebellar lesions induce ipsilateral signs, although expanding lesions may produce a false localization of clinical signs.

2. Diffuse cerebellar disorders, such as degenerative ataxias, are usually responsible for relatively symmetric deficits.

3. Cerebellar deficits due to non-progressive disease tend to undergo attenuation with time.

4. Lesions involving the afferent or efferent cerebellar pathways outside the cerebellum may generate cerebellar-like deficits.

5. Cerebellar symptoms are influenced more by the location and rate of progression of the disease than by the pathological characteristics . Slowly progressive lesions may be remarkably asymptomatic for a long time, while rapidly expanding lesions are associated with severe symptoms in most cases.

SIGNSCharcot’s neurologic triad is the combination of nystagmus, intention tremor, and scanning or staccato speech. Similar to charcot’s triad of cholangitis (fever, RUQ pain and jaundice).

Clinical Signs as a Function of Sagittal Zone Affected

Vermal Zone Paravermal Zone Lateral Zone

Oculomotor deficits

Dysarthria Oculomotor deficits

Dysarthria Dysarthria

Head tilt Head tilt

Ataxia of stance Dysmetria

Ataxic gait Kinetic tremor

Titubation Action tremor Hypotonia Dysdiadochokinesia Decomposition of movements Dysrhythmokinesia Impaired check/rebound Ataxia of stance Ataxia gait

Cerebellar Cognitive Affective SyndromeAdults with large unilateral or bilateral cerebellar lesions that involve the posterior lobe manifest a constellation of cognitive, affective and behavioral abnormalities that are clinically relevant and detectable on bedside mental state tests. Deficient executive functions include working memory, motor or ideational set shifting, and perseveration of actions or drawings; and impairment



of verbal fluency that manifests as telegraphic speech. In some cases the speech impairment is severe enough to resemble mutism. Visuospatial disintegration may appear as difficulty copying and conceptualizating drawn images.[6] Simultanagnosia; anomia; agrammatism and dysprosodia; deficient mental arithmetic; and mildly abnormal verbal and visual learning and recall may also be found. The constellation of executive, visual spatial and linguistic changes forms the core of the intellectual deficits of the CCAS.

Episodic AtaxiasCharacterized by recurrent episodes of vertigo and ataxia variably with progressive ataxia,also called Hereditary Episodic Ataxia. It is classically sudden in onset and manifests in childhood or early adulthood as lack of co-ordination,impaired speech and occulomotor disturbances. Usually lasts for minutes to hours.[7] It is not associated with any impairment of consciousness. It is dinstinctive in its clear onset and clear resolution rather than waxing/waning course. EA 2 is associated with migraine, fluctuating weakness, nausea/vomiting, seizures and dystonia. Attacks are typically brief lasting for seconds to minutes.

Diagnosis and InvestigstionsCerebellar disorders have characteristic symptoms and classical signs but appearance of signs and symptoms depend on the extent of lesion.[8] The patient may present with full blown picture of ataxia or display only the non motor symptoms.

Investigations 1. Routine Blood Tests2. CT Scan/ MRI Brain: Form the gold standard tests3. CSF Analysis, NCV, Evoked Potentials: Supportive4. Serum Vitamin E Estimation: Decreased levels

assocoiated with ataxia. Increased plasma levels of cholestanol in cerebrotendinous xanthomatosis and impaired copper metabolism occur in Wilson disease

5. Immunoglobulin Testing: Viral infecetions and celiac disease

6. Thyroid Function Tests7. Bone Marrow Study: Lysosomal storage diseases

Role of Genetic TestingGenetic testing can be used not only for diagnosis, but also for pre-natal evaluation, predictive testing, and carrier testing (for relatives of patients with X-linked or autosomal recessive ataxia).

Pre-natal testing requires tissue obtained by amniocentesis or chorionic villous biopsy. Such procedures require a clear understanding of the risks and outcomes of the tests. The decision to terminate the pregnancy as a result of these tests should be provided by a genetic counselor and an obstetrician or gynaecologist.[9] Preimplantation testing with subsequent implantation of embryos free of any mutation should be carefully discussed with the family.

Management• Most important step is to investigate the cause

and extent of involvement.• Significant number of diseases are curable and a

nmber of them are manageable• Early evaluation and intervention is the rule• Acute cerebellitis due to viral infection has got full

recovery without any long lasting complication. Usually ataxia self improves within weeks to months

• Ataxia due to intoxication is potentially treated in most cases

• Alcohol produce widespread effect on brain which includes cerebellum, mammillary bodies, hippocampus, cerebral cortex. In early cases cerebellar ataxia is usually reversible.

• Cerebellar haemorrhage is a neurosurgical emergency, where early intervention (>3 cm diameter) is lifesaving and rewarding.

• Vascular infarct needs therapy with antiplatelet drugs, antidyslipidemic agents and early osmotherapy.

• Patients manifesting paraneoplastic ataxia should be evaluated for underlying primary.

• Celiac disease sufferers should be placed on gluten free diet.

• Daily supplementation with Vitamin E & folate.[10]

• Chelators and Zinc supplementation for Wilson disease

Restriction of phytanic acid in refsum disease (ataxia, scaly skin (ichthyosis), difficulty hearing, and eye problems including cataracts and night blindness).[11]

Thyroid hormone supplementation to correct Hypothyroidism

Caution with the use of drugs that may exacerbate ataxia eg, valproate, phenytoin, amiodarone, INH, mefloquine, cimetidine, etc.[12]

For EA, acetazolamide 125–500 bid used, alternatively 4-aminopyridine, carbamazepine or phenytoin may be used



Drugs Suggested for Cerebellar Symptoms in Adults

Symptom Drug

Cerebellar ataxia Amantadine (release of dopamine and modulation of NMDA pathway) 50–300g/day Buspirone (5-HT1A agonist) 10–60 mg/day Tandospirone (5-HT1A agonist) 15–30 mg/day D-cycloserine (partial NMDA receptor allosteric agonist) 50 mg/day L-tryptophan (precursor of 5-HT) 600–1000 mg/day

Tremor Propranolol (beta-blocker) 80–240 mg/day Clonazepam (benzodiazepine derivative) 2–8 mg/day Ondansetron (5-HT3 antagonist) 4–16 mg/day Primidone (interactions with voltage-gated sodium channels) 250–500 mg/day Pregabalin (acting on α2δ subunit of the volgage-dependent calcium channel) 75–300mg/day

Nystagmus Gabapentin (GABA analog) 900–4200 mg/day Clonazepam 0.5–3 mg/day 3,4-diaminopyridine 40–80 mg/day Baclofen (GABA-B receptor agonist) 20–80 mg/day Memantine (uncompetitive NMDA antagonist) 5–20 mg/day

SurgeryDecompressive interventions for cerebellar

hemorrhages> 3 cm diameter is indicated.[13]

Congenital malformation needs correctionNeurosurgery is the mainstay for Posterior fossa tumorsIn selected cases DBS (Vim) may improve and relieve

tremors (though not as rewarding as in Parkinson’s disease).[14]

Therapeutic Strategies under Investigation

Strategles Experimental Observations and Results

Reducing the oxidative stress

Increased aggregation and cell death under oxidative stress in human mutant ataxin-1 expressing cells (Kim et al., 2003). Antioxidants show some benefit in mouse models of Huntington disease (Beal & Ferrante, 2004)

Acting on the excitotoxic cascade

NMDA receptor antagonists improve survival in mouse models of Huntington disease (Ferrante et al., 2002)

Silencing gene expression via RNA interference

Reduction of aggregates and phenotypic improvements in mouse models of SCA1 (Zu et al., 2004; Xia et al., 2004)

Enhancing the clearance of the mutant protein

Rescue in cell, fly and mouse models of Huntington disease (Ravikumar et al., 2004)

Targeting the toxicity of the protein via modulation of phosphorylation

Favorable effect on ataxia in SCA1 mice (Kaytor et al., 2005; Emamian et al., 2003)

Acting on chaperones Over expression of HSP70 decreases the toxicity of ataxin 1 in cells, files and mice (Cummings et al., 2001)

Inhibition of transglutaminases

Cystamine decreases toxicity in cell models of DRPLA and mouse models of Huntington disease (Karpuj et al., 2002)

Acting on transcriptional regulation

Mutant polyglutamine-expanded ataxin 7 inhibits the histone acetyltransferase function (Palhan et al., 2005) Improved neuropathology and motor phenotypes in fly and mouse models of Huntington disease treated with histone deacetylase inhibitors

Inhibition of caspase activation

Favorable effects of caspase inhibitors in mouse models of Huntington disease (Chen et al., 2000)

Transplantation Graft survival and behavioural improvements in SCA-1 transgenic mice (Kaemmerer & Low, 1999)

ConclusionThe terminology of cerebellar ataxias encompasses a wide range of disorders. The advances in Neuroimaging, the progress in translational neurosciences, the recent discoveries in molecular biology, and the availability of genetic testing have revolutionized the field of cerebellar Ataxias. In particular, the identification of the causative mutations of many ataxias has influenced daily practice worldwide. Since the clinical diagnosis of subtypes of ataxias is often complicated by the salient overlap of the phenotypes between genetic subtypes, and given the numerous disorders affecting the cerebellum, many students, biologists, clinicians,and researchers often experience difficulties in the discipline of cerebellar ataxias. Making the right diagnosis remains a major goal when facing a growing number of disorders which look apparently similar. The last decades have brought a growing number of demonstrations that the cerebellum participates in non-motor activities. The contributions of cerebellar circuitry in the so-called cognitive operations, including executive functions,emotions, learning, and language are noteworthy.

References1. Brains Neurology, 5th Edition, p. 980.2. Harrisons PIM, 18th Edition, Chapter 373.3. Cerebellar Disorders-A Practical Approach to Diagnosis and

Management, 2010.4. The Cerebellum, Aug. 2011.5. Handbook of the Cerebellum and Cerebellar Disorders, Springer

6 Etherlands (2013).6. Snell Neuroanatomy, 7th Edition, 2010 Chapter 6.7. Adam and Victor’s Neurology, 10th Edition, p. 81.8. Clinical Neuroanatomy Lange, 26th Edition, Chapter 7, p. 79. 9.



ATHETOSIS: Slow involuntary writhing movements of finger, hands, toes & feet (distal extremeties). In

some cases it also involves arm, leg, neck and tongue.Causes: Lesion in corpus striatum, hippocampus &

thalamus.

Usually seen as a feature of cerebral palsy.Association: Hypotonia, difficulty in maintenance of

posture.Treatment: No definite therapy. However diazepam,

haloperidol, trihexyphenidyl (pacitane) and benztropine (cogentin).

Chorea: Semi-directed, irregular movements that are not repetitive or rhythmic, but appear to flow from one muscle to the next.

These ‘dance-like’ movements of chorea often occur with athetosis, which adds twisting and writhing movements. Walking may become difficult, and include odd postures and leg movements. Occurs without conscious effort.

Cause: Lesion in corpus striatum. Eg.Huntington disease, choreagravidarum, sydenham’s chorea secondary to rheumatic fever, Wilsondisease, neuroacanthocytosis (peripheral neuropathy, cardiomyopathy, haemolyticanemia).

Treatment: No definite therapy, ususally control of the underlying disease provides some relief.

Ballism: Characterized by fast flaying undesired movement of limbs and repeated movements usually involving proximal parts of limb.

Cause: Lesion of Subthalamic nucleus of basal ganglia. Most common cause is stroke. Rarely it may be secondary to traumatic brain injury, amyotrophic lateral sclerosis, hyperglycemia, tuberculoma, HIV, etc.

Medical Management Includes Antidopaminergiv Drugs Like Haloperidol, Chlorpromazine: Anticonvulsants like topiramate: Intrathecal baclofen: Botox injection

Invasive Modalities: Deep brain stimulation of GPi: stereotactic neurosurgery

DYSKINESIA: Involuntary muscle movements,[1]

including movements similar to tics or chorea and diminished voluntary movements.[2] Dyskinesia can be anything from a slight tremor of the hands to an uncontrollable movement of the upper body or lower extremities.

1,2Associate Professor, Department of Medicine, JN Medical College, AMU, Aligarh–202002, U.P., India3Professor and Chairman, Department of Medicine, JN Medical College, AMU, Aligarh–202002, U.P., India

Abnormal MovementsDr. Anjum Mirza Chughtai1, Dr. Muhammad Uwais Ashraf2 and Prof . M.R. Ajmal3

ABSTRACTMovement disorders encompass a vast area of Neurologic literature and it is indeed an exhaustive task to compile in short various forms of movement disorders. No single textbook seems sufficient to give a complete overview of movement disorders in Neurology. Therefore, we have done a modest effort to bring different movement disorders in a nutshell in this review article. Different types of movement disorders can be classified depending upon their frequency, regularity, relation with sleep and stress and associated neurologic findings. An effort has been made to keep this review article as simple and lucid as possible.

Review Article



Medication Induced Dyskinesia: Off period dyskinesia (low l-dopa plasma levels): diphasic dyskinesia (levels of l-dopa rising): peak dose dyskinesia (plateau of l-dopa levels): tardive dyskinesia (occurs after long term treatment with high potency antipsychotic drugs).

Treatment involves withdrawal of the offending drug and treatment of underlying disorder with dose adjustments.

TORSION DYSTONIA

TREMORS: Involuntary, rhythmic, muscle contraction and relaxation involving to and from movements (oscillations or twitching) of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the hands.

Causes: Multiple sclerosis, stroke, traumatic brain injury, chronic kidney disease and a number of neurodegenerative diseases that damage or destroy parts of the brainstem or the cerebellum, Parkinson’s disease, drugs (such as amphetamines, cocaine, caffeine, corticosteroids, SSRI), mercury poisoning; or the withdrawal of drugs such as alcohol or benzodiazepine.

Etiology & Management • Cerebellar tremor (aka intention tremor, (6–8

Hz variable amplitude)) most prominent when the affected person is active or is maintaining a particular posture. Associated with ataxia, dysarthria (speech problems), nystagmus (rapid, involuntary rolling of the eyes), gait problems and postural tremor of the trunk and neck. Decrease with alcohol, benzodiazepines.

• Dystonic tremor• Essential Tremor: ((6–8 Hz variable amplitude)benign

tremor or familial tremor or shaky hand syndrome) is the most common movement disorder. Includestremor of the arms, hands or fingers but sometimes involving the head or other body parts during voluntary movements such as eating and writing. treated with primidone, propranolol, atenolol, nadolol, topiramate, benzodiazepine.

• Parkinson Tremor: Rest tremor in the hand is often described as ‘pill rolling’. measures between 4.5 and 5.5 cycles per second, variableamplitude.treated with anticholinergics like trihexyphenidyl, benztropine.

• Physiological Tremor: Occurs in every normal individual and has no clinical significance. beta blockers provide symptomatic relief.

• Psychogenic Tremor: (hysterical tremor), can occur at rest, certain postures or movements.

• Rubral Tremor: Coarse slow tremor which is present at rest, at posture and with intention. This tremor is associated with conditions which affect the red nucleus in the midbrain, classically unusual strokes.

Ataxia: Gross lack of coordination of muscle movements

Akathisia: Inability to sit stillBlepharospasm: Uncontrolled eyelid spasm



Writer’s Cramp: Mogigraphia and scrivener’s palsy, causes a cramp or spasm affecting certain muscles of the hand and/or fingers.

Spasmodic Torticollis: Twisting of head and neck

Titubation: Tremors of head or neck causing nodding movements

Geniospasm: Episodic involuntary up and down movements of the chin and lower lip.

Fasciculation: Abnormal miscle twitching of small muscle fibres usually seen in thighs , arms caused by degeneration of anterior horn cells as in Motor Neuron Disease.

Myoclonus: Brief, involuntary twitching of a muscle or a group of muscles

TICS: Involuntary, compulsive, repetitive, stereotypedMyokymia: Involuntary, spontaneous, localised

quivering of a few muscles, or bundles within a muscle, but which are insufficient to move a joint.

Muscle Spasm: Sudden, involuntary contraction of a muscle, a group of muscles.

Anatomical Parts Involved in Specific Diseases

ATROPHY OF STRIATUM INVOLVED IN CHOREA,

CHOREOATHETOSIS,DYSKINESIA

LESION IN SUBTHALAMIC NUCLEUS CAUSES HEMIBALLISM

DEATH OF DOPAMINERGIC NEURONS IN THE PARS

COMPACTA OF THE SUBSTANTIA NIGRA RESULTS IN PARKINSON’S

DISEASE



References1. Yokoyama, T., Ryu, H., Uemura and Athetosis, K. (1993),

Nihon Rinsho, Nov., Vol. 51(11), pp. 2855–8.2. Bhidayasiri, R., Truong, D.D. (2004), “Chorea and Related

Disorders, Postgrad Med J., Sep., Vol. 80(947), pp. 527–534.3. Burnett, L., Jankovic, J. Chorea and ballism (1992), Curr

Opin Neurol Neurosurg, Jun, Vol. 5(3), pp. 308–13.4. Soares-Weiser, K., Fernandez, H.H. (2007), “Tardive

dyskinesia”, Semin Neurol, Apr., Vol. 27(2), pp. 159–69.5. Elias, W.J. and Shah, B.B. (2014), Tremor, JAMA, Mar 5,

Vol. 311(9), pp. 948–54.

6. Marsden, C.D. and Sheehy, M.P. (1990), “Writer’s Cramp”, Trends Neurosci, Apr., Vol. 13(4), pp. 148–53.

7. Danek, A. (1993), “Geniospasm: Hereditary Chin Trembling”, Mov Disord., Jul, Vol. 8(3), Vol. 335–8.

8. Reimers, C.D., Ziemann, U. and Scheel, A. et al. (1996), “Fasciculations: Clinical, Electromyographic, and Ultrasonographic Assessment”, J Neurol. Aug, Vol. 243(8), pp. 579–84.



1,3Senior Resident, Department of Endocrinology and Metabolism, Institute of Medical Sciences, Banaras Hindu University, Varanasi–221005, India2Professor and Head, Department of Endocrinology and Metabolism, Institute of Medical Sciences, Banaras Hindu University, Varanasi–221005, IndiaE-mail: [email protected]

Diabetic Charcot OsteoarthropathyBhandari S.1, Agrawal N.K.2 and Nath M.3

ABSTRACTMovement disorders encompass a vast area of Neurologic literature and it is indeed an exhaustive task to compile in short various forms of movement disorders. No single textbook seems sufficient to give a complete overview of movement disorders in Neurology. Therefore, we have done a modest effort to bring different movement disorders in a nutshell in this review article. Different types of movement disorders can be classified depending upon their frequency, regularity, relation with sleep and stress and associated neurologic findings. An effort has been made to keep this review article as simple and lucid as possible.

Review Article

Introduction

Charcot osteoarthropathy (COA) is a rare progressive disorder of the musculoskeletal system that is

characterized by joint dislocations, pathologic fractures, and debilitating deformities.[1-3] It was first described by J.K. Mitchell, American physician in 1831 as secondary to tuberculosis induced spinal damage but named after Jean-Martin Charcot, French neurologist (1868) who described this entity in tabes dorsalis patients.[4]

EpidemiologyThe association between Charcot’s joint disease and diabetes mellitus was first established by William Reily Jordan (1936) in a comprehensive paper entitled “Neuritic Manifestations in Diabetes Mellitus,[5]” The most common cause of COA in today’s world is diabetic neuropathy. Other causes include leprosy, polio myelitis, syringomyelia, alcohol abuse, traumatic injury, multiple sclerosis, hea vy metal poisoning, congenital neuropa thy and rheumatoid arthritis.[6-7]

Worldwide, the prevalence of Charcot neuroarthropathy due to diabetes mellitus is 0.08% to 7.5%.[8-11] A prospective study of 1666 patients in Texas from a disease management program reported that the incidence was 8.5/1000 per year.[12]

The mean duration of diabetes before the diagnosis is 15 years.[8,9,11] These patients present in fourth or fifth decade.[8,9,11,13-16] So age is not as important a factor as the duration of diabetes mellitus in the development of Charcot osteoarthropathy. Bilateral involvement occurs in 5.9% to 39.3%.[15,16] Both type 1 (T1DM) and type 2 diabetes (T2DM) patients are at risk, but the former is present at a slightly earlier age.[14]

Pathogenesis Multiple factors appear to contribute to the development of bone and joint destruction in people with diabetes. Two theories have been proposed to explain the pathogenesis: ‘French theory’ the ‘German theory’.

German TheoryVolkman and Virchow proposed the ‘German theory,’ which suggested that multiple subclinical trauma in a denervated joint were the initial precipitating factor.[18]

Peripheral neuropathy with loss of protective sensation and repetitive micro trauma may initiate the process.

French TheoryCharcot proposed the ‘French theory’, wherein the joint deformity was attributed to damaged central nervous system centers that control bone and joint nutrition17

Support for the hypothesis that increased blood flow and active bone resorption are responsible for the development of Charcot joint is evidenced by several case reports and experimental data.[9,10 19-22]

Lippman and colleagues[23] suggested that excess local arterial flow can be a factor contributing to osseous breakdown under stress.

Archer and colleagues,[24] at King’s College Hospital, London, measured resting foot blood flow in 22 diabetic patients with severe sensory neuropathy using mercury strain gauge plethysmography and Doppler sonogram techniques. They found blood flow to be increased on average five times greater than normal, at 20° to 22ºC. They noted that foot skin temperature was also elevated, reflecting the increased circulation.

Autonomic neuropathy with increased blood flow to bone, cause arteriovenous shunting, and may lead to bone resorption, weakening, fracture, and deformation with continued walking.

Other factors that may play a role in the development of the diabetic Charcot foot are metabolic abnormalities that weaken bone, renal disease, renal transplantation, and immunosuppressive treatment, glycosylation of collagen, proinflammatory cytokines RANKL/OPG signaling pathway.

Anatomical Classification On the basis of Anatomic patterns of bone and joint destruction Sanders and Frykberg proposed the classification.[25-27]



Pattern Joints Involved PrevalenceI Forefoot: interphalangeal joints,

phalanges, metatarsophalangeal joints, or distal metatarsal bones.

26%–67%

II Tarsometatarsal Joints 15%–48%III Naviculocuneiform, Talonavicular,

and Calcaneocuboid Joints 32%

IV Ankle and Subtalar Joints 3%–10% V Calcaneus 2%

The most frequent joint involvement is seen in patterns I, II, and III, and the most severe structural deformity and functional instability are seen in patterns II and IV. Pattern V osteopathy is the least common and may be seen as an isolated fracture of the calcaneus or in association with involvement of other tarsal bones

Diagnosis Clinical Features As early as 1931, Steindler recognized the need for early detection of the neuropathic joint and the importance of immediate protection to prevent further deterioration of the articulation.[28]

Harris and Brand held a similar opinion,

also recognizing the possible need for surgical stabilization should cast immobilization be ineffective in arresting the complete disintegration of the involved joints.[29]

There should be high index of clinical suspicion in the patient with diabetes mellitus and peripheral neuropathy who presents with new-onset swelling, erythematic, and increased warmth of the foot and ankle.[6]

Acute Charcot OsteoarthropathyPatient presents either as an acute or a chronic arthropathy. The acute phase is usually precipitated by minor trauma, which generally goes unrecognized by the patient.[30] On examination, Skin temperature of the affected foot has been reported to be elevated approximately 5°C. The pedal pulse on the affected side may be bounding.[6]

Handheld infrared dermal thermometers is used to assess skin temperature differences, monitoring of healing (associated with ‘foot cooling’) and recurrence (associated with ‘foot warming’).[31]

This stage is difficult to distinguish from acute gouty arthritis, septic arthritis, cellulites, rheumatoid arthritis, nonspecific asymmetric venous swelling.

The acute phase may last for several months to subside, and is followed by a painless foot.

Chronic Charcot OsteoarthropathyTemperature elevation and redness gradually subside, while permanent deformities may develop which includes arch collapse with rocker bottom deformity. As patient continues standing and walking, high pressures make these patients prone to ulceration. Finally, ulcerated areas may become infected and infection may spread to the bone, leading to osteomyelitis.

Imaging Diagnosis should be confirmed by imaging. X ray foot is the primary initial imaging method, which may be normal or show subtle fractures and dislocations or overt fractures.[32]

In the presence of a foot ulcer osteomyelitis should be ruled out. MRI is being increasingly used for the diagnosis of early sta ges in Charcot Osteoarthropathy.[33] In acute Charcot Osteoarthropathy, T1 sequence shows reduced signal intensity and increased signal intensity on T2 sequence. In Chronic Charcot Osteoarthropathy, there is diffusely diminished marrow signal intensity and cyst formation.[34] MRI may help in distinguishing Charcot Osteoarthropathy from osteomyelitis in some cases.[35]

Three-phase[99] mtc bone scintigraphy (85%) and 111 In labeled leukocyte scintigraphy, Positron emission tomography (PET) are sensitive but unreliable techniques to distinguish between osteomyelitis and Charcot Osteoarthropathy.[36]

Treatment and Management Medical TreatmentFor acute Charcot foot the mainstay of treatment is Immobilization and reduction of weight-bearing stress by offloading the foot, treating bone disease, and preventing further foot fractures.

At least 8 to 12 weeks of no weight-bearing cast immobilization is required to convert the active inflammatory arthritis to the quiescent phase.

Armstrong and colleagues[44] in a study of[55] patients with acute Charcot foot reported an average total-contact casting duration of 18.5 weeks. After ambulatory total-contact casting, the patients were weaned into a removable cast walker prior to wearing accommodative footwear.

Off-loading is done by non-weight-bearing or limited weight bearing with a plaster cast, bivalved cast, prefabricated removable walker boot with a rigid rocker sole and custom insole, or total-contact cast. The gold standard of of floading is the total contact cast (TCC).[6,38,39]

Prognosis for optimal function is best when deformity, ulcers, and contralateral involvement are avoided.[39]

Antiresorptive Therapy There is little evidence to support the use of bisphosphonates. The rationale behind their use is that bone turnover in patients with active Charcot Osteoarthropathy is excessive.

Pitocco and coinvestigators[40] recently evaluated the efficacy of alendronate. The patients received a total-contact cast boot for 2 months, followed by a pneumatic walker for 4 months. After 6 months, there was a significant reduction in bone markers (ICTP and hydroxyprolin) and an increase in bone density in the test group. Jude and co-investigators41 studied the effects of bisphosphonate pamidronate in the treatment of acute Charcot osteoarthropathy. They found that with a single



dose pamidronate led to a reduction in bone turnover, symptoms, and disease activity.

Intranasal calcitonin was associated with a significantly greater reduction in cross-linked carboxy-terminal telopeptide of type I collagen and bone-specific alkaline phosphatase.

Also, there have been no published reports to date on the efficacy of salmon calcitonin for the treatment of acute Charcot’s osteoarthropathy.

Surgery Instability, deformity, chronic ulceration, and progressive joint destruction, despite rest and immobilization, are the primary indications for surgical intervention.[14,17]

Pinzur[42] did a retrospective study on 198 patients (201 feet) with Charcot osteoarthropathy treated over a 6-year period. After a minimum 1-year follow-up, 59.2% with midfoot involvement achieved the desired endpoint (long-term management with therapeutic footwear and orthoses) without surgical intervention, whereas 40% required surgery.

Surgical options include debridement of ulcers to remove necrotic and infected tissue; excision of bony prominences (ostectomy) that may cause an ulcer; and reconstruction with osteotomy and arthrodesis for correction of fixed deformity or severe instability to enable successful brace treatment.[43]

Summary A high index of suspicion for this disorder will often lead to early diagnosis and prevent progressive deformity by prompt treatment. The Charcot’s joint disease is suspected when a neuropathic patient presents with an inflamed and/or deformed foot, especially following a minor injury. Plain radiographs should be taken when a neuropathic patient presents with a swollen foot. If radiographs are negative but suspicion for the disease is high, repeat the radiographs at 10 to 14 days. If still equivocal, MRI or bone scan may be considered.

Off-loading and total contact casting are the mainstay for treatment. The patients with Charcot foot are at risk for future pedal complications and contralateral involvement and therefore require life- long surveillance.

Legends

Fig. 1: The Charcot Midfoot Fracture Dislocation, Collapse of the Arch and

Rocker Bottom Midfoot Deformity

Fig. 2: 6 D’s in Xray of Pattern III Charcot Osteoarthropathy: Density (Increased),

Dislocation, Destruction, Distension, Debris and Disorganization

Fig. 3: Pattern IV Charcot Osteoarthropathy: Extensive Bony Destruction, Joint Distension, Loss of Fat Planes, Bony Erosion and Adjacent Sclerotic Changes with Bony Fragments

Noted in Distal Tibial Bone, Ankle Joint and Tarsometatarsal Joint

References1. Trepman, E., Nihal, A. and Pinzur, M.S. (2005), “Current

Topics Review: Charcot Neuroarthropathy of the Foot and Ankle”, Foot Ankle Int., 2005 Jan, Vol. 26(1), pp. 46–63.

2. Brodsky, J.W. (1999), “The Diabetic Foot”, In Surgery of the Foot and Ankle, 7th edn (eds Coughlin, M.J. & Mann, R.A.) pp. 895–969 (Mosby, St Louis, 1999).

3. Eichenholtz, S.N. Charcot Joint, (Charles C. Thomas, Springfield, Illinois, 1966).

4. Gupta, R. (1993), “A Short History of Neuropathic Arthropathy”, Clin Orthop Relat Res., 1993 Nov., Vol. 296, pp. 43–9.

5. Jordan, W.R. (1936), “Neuritic Manifestations in Diabetes Mellitus”, Arch Intern Med., Vol. 57, pp. 307–366.

6. Wukich, D.K. and Sung, W. (2009), “Charcot Arthropathy of the Foot and Ankle: Modern Concepts and Management Review”, J. Diabetes Complications, Vol. 23, pp. 409–426.

7. Mabilleau, G. and Edmonds, M.E. (2010), “Role of Neuropathy on Fracture Healing in Charcot Neuro-osteoarthropathy”, J. Musculoskelet Neuronal Interact, Vol. 10, pp. 84–91.

8. Bailey, C.C. and Root, H.F. (1947), “Neuropathic Foot Lesions in Diabetes Mellitus, N. Engl. J. Med., Vol. 236(11), pp. 397–401.

9. Forgacs, S. (1976), “Clinical Picture of Diabetic Osteoarthropathy”, Acta Diabetol Lat., Vol. 3(3–4), pp. 111–129.

10. Pogonowska, M.J., Collins, L.C. and Dobson, H.L. (1967), “Diabetiosteopathy”, Radiology, Vol. 89, pp. 265–271.

11. Sinha, S., Munichoodappa, C.S. and Kozak, G.P. (1972), “Neuro-arthropathy (Charcot joints) in Diabetes Mellitus (Clinical Study of 101 Cases)”, Medicine (Baltimore), Vol. 51(3), pp. 191–210.

12. Lavery, L.A., Armstrong, D.G. and Wunderlich, R.P. et al. (2003), “Diabetic Foot Syndrome: Evaluating the Prevalence and Incidence of Foot Pathology in Mexican Americans and non-Hispanic Whites from a Diabetes Disease Management Cohort”, Diabetes Care, Vol. 26(5), pp. 1435–1438.

13. Armstrong, D.G., Todd, W.F. and Lavery, L.A. et al. (1997), “The Natural History of Acute Charcot’s Arthropathy in a Diabetic Foot Specialty Clinic”, J. Am Podiatr. Med. Assoc., Vol. 87(6), pp. 272–278.

14. Clohisy, D.R. and Thompson, R.C. (1988), “Jr: Fractures Associated with Neuro-pathic Arthropathy in Adults Who have Juvenile-onset Diabetes”, J. Bone Joint Surg. Am., Vol. 70(8), pp. 1192–1200.



15. Clouse, M.E., Gramm, H.F., Legg, M. and Flood, T. (1974), “Diabetic Osteoarthropathy: Clinical and Roentgenographic Observations in 90 Cases”, Am J. Roentgenol Radium Ther Nucl. Med., Vol. 121(1), pp. 22–34.

16. Sanders, L.J. and Mrdjenovich, D. (1991), “Anatomical Patterns of Bone and Joint Destruction in Neuropathic Diabetics”, Diabetes, Vol. 40(suppl 1), p. 529A.

17. Edmonds, M.E., Roberts, V.C. and Watkins, P.J. (1982), “Blood Flow in the Diabetic Neuropathic Foot”, Diabetologia, Vol. 22, pp. 9-15.

18. Rajbhandari, S.M., Jenkins, R.C., Davies, C. and Tesfaye S. (2002), “Charcot Neuroarthropathy in Diabetes Mellitus”, Diabetologia, Vol. 45, pp. 1085–1096.

19. Jeffcoate, W.J., Game, F. and Cavanagh, P.R. (2005), “The Role of Proinflammatory Cytokines in the Cause of Neuropathic Osteoarthropathy (Acute Charcot Foot) in Diabetes”, Lancet, Vol. 366(9502), pp. 2058–2061.

20. Craig, J.G., Amin, M.B. and Wu, K. et al. (1997), “Osteomyelitis of the Diabetic Foot: MR Imaging-pathologic Correlation”, Radiology, Vol. 203(3), pp. 849–855.

21. Lavery, L.A., Higgins, K.R. and Lanctot, D.R. et al. (2004), “Home Monitoring of Foot Skin Temperatures to Prevent Ulceration”, Diabetes Care, Vol. 27(11), pp. 2642–2647.

22. Kelly, P.J. and Coventry, M.B. (1958), “Neurotrophic Ulcers of the Feet: Review of Forty-seven Cases”, J. Am Med. Assoc., Vol. 168(4), pp. 388–393.

23. Lippmann, H.I., Perotto, A. and Farrar, R. (1976), “The Neuropathic Foot of the Diabetic”, Bull N.Y. Acad. Med., Vol. 52(10), pp. 1159–1178.

24. Archer, A.G., Roberts, V.C. and Watkins, P.J. (1984), “Blood Flow Patterns in Diabetic Neuropathy”, Diabetologia, Vol. 27, p. 563.

25. Sanders, L.J. and Mrdjenovich, D. (1991), “Anatomical Patterns of Bone and Joint Destruction in Neuropathic Diabetics”, Diabetes, Vol. 40(suppl 1), p. 529A.

26. Frykberg, R.G. and Kozak, G.P. (1995), “The Diabetic Charcot Foot”, In Kozak, G.P., Campbell, D.R., Frykberg, R.G., Habershaw, G.M. (eds) Management of Diabetic Foot Problems, 2nd ed. Philadelphia: WB Saunders, pp. 88–97.

27. Sanders, L.J. and Frykberg, R.G. (1991), “Diabetic Neuropathic Osteoarthropathy: The Charcot Foot”, In Frykberg, R.G. (ed) The High Risk Foot in Diabetes Mellitus, New York: Churchill Livingstone, pp 297–338.

28. Steindler, A. (1931), The Tabetic Arthropathies, JAMA Vol. 96, pp. 250–256.

29. Harris, J.R. and Brand, P.W. (1966), “Patterns of Disintegration of the Tarsus in the Anaesthetic Foot”, J. Bone Joint Surg. Br., Vol. 48(1), pp. 4–16.

30. Chantelau, E., Richter, A., Schmidt-Grigoriadis, P. and Scherbaum, W.A. (2006), “The Diabetic Charcot Foot: MRI Discloses Bone Stress Injury as Trigger Mechanism of Neuroarthropathy”, Exp ClinEndocrinol Diabetes, Vol. 114, pp. 118–123

31. Armstrong, D.G., Lavery, L.A. and Liswood, P.J. et al. (1997), “Infrared Dermal Thermometry for the High-risk Diabetic Foot”, Phys Ther., Vol. 77(2), pp. 169–175, discussion 176–167.

32. Gold, R.H., Tong, D.J., Crim, J.R. and Seeger, L.L. (1995), “Imaging the Diabetic Foot”, Skeletal Radiol, Vol. 24, pp. 563–571.

33. Chantelau, E. and Poll, L.W. (2006), “Evaluation of the Diabetic Charcot Foot by MR Imaging or Plain Radiography—An Observational Study”, Exp ClinEndocrinol Diabetes, Vol. 38, pp. 361–367.

34. Tan, P.L. and Teh, J. (2007), “MRI of the Diabetic Foot: Differentiation of Infection from Neuropathic Change”, Br. J. Radiol, Vol. 80, pp. 939–948.

35. Beltran, J., Campanini, D.S., Knight, C. and McCalla, M. (1990), “The Diabetic Foot: Magnetic Resonance Imaging Evaluation”, Skeletal Radiol., Vol. 19, pp. 37–41.

36. Palestro, C.J. et al. (1998), “Marrow Versus Infection in the Charcot Joint: Indium111 Leukocyte and Technetium99m Sulfur Colloid Scintigraphy”, J. Nucl. Med., Vol. 39, pp. 346–350.

37. Stefansky, S.A. and Rosenblum, B.I. (2005), “The Charcot Foot: A Clinical Challenge”, Int. J. Low Extrem Wounds, Vol. 4, pp. 183–187.

38. VanderVen, A., Chapman, C.B. and Bowker, J.H. (2009), “Charcot Neuro-arthropathy of the Foot and Ankle”, J. Am Acad. Orthop. Surg., Vol. 17, pp. 562–571.

39. Pitocco, D., Ruotolo, V., Caputo, S., Mancini, L., Collina, C.M., Manto, A., Caradonna, P. and Ghirlanda, G. (2005), “Six-month Treatment with Alendronate in Acute Charcot Neuroarthropathy: A Randomized Controlled Trial”, Diabetes Care, 2005 May, Vol. 28(5), pp. 1214–5.

40. Jude, E.B., Selby, P.L., Burgess, J., Lilleystone, P., Mawer, E.B., Page, S.R., Donohoe, M., Foster, A.V., Edmonds, M.E. and Boulton, A.J. (2001), “Bisphosphonates in the Treatment of Charcot Neuroarthropathy: A Double-blind Randomised Controlled Trial”, Diabetologia, Vol. 44(11), pp. 2032–2037.

41. Pinzur, M. (2004), “Surgical Versus Accommodative Treatment for Charcot Arthropathy of the Midfoot”, Foot Ankle Int., Vol. 25(8), pp. 545–549.

42. Stefansky, S.A. and Rosenblum, B.I. (2005), “The Charcot Foot: A Clinical Challenge”, Int. J. Low Extrem Wounds, Vol. 4, pp. 183–187.

43. Armstrong, D.G., Stacpoole-Shea, S., Nguyen, H. and Harkless, L.B. (1999), “Lengthening of the Achilles Tendon in Diabetic Patients Who are at High Risk for Ulceration of the Foot”, J. Bone Joint Surg. Am., Vol. 81, pp. 535–538.



Diabetes is characterized by the development of specific microvascular complications and a high incidence of accelerated atherosclerosis1,4. The Microvasular and Macrovascular complications are related to Hyperglycemia, its extent and duration. Dysglycemia, classically has two components: chronic sustained hyperglycemia and acute glycemic fluctuations from peaks to nadirs. Both components lead to diabetes complications through two main mechanisms: excessive protein glycation and activation of oxidative stress. A few years ago, these two mechanisms were unified in an elegant theory that suggested that the glycemic disorders observed in diabetic patients result in an activation of oxidative stress with an overproduction of superoxide by the mitochondrial electron-transfer chain5,6. This activation in turn produces a cascade of such deleterious metabolic events as enhanced polyol activity, increased formation of advanced glycation end products, activation of protein kinase C and nuclear factor κB, and increased hexosamine pathway flux 5, 6. It is now well established that hyperglycemia both at fasting and during postprandial periods results in exaggerated and accelerated glycation. all the studies conducted in type 1 and type 2 diabetes have clearly shown a strong positive relationship between A1C levels and plasma glucose levels at fasting and over postprandial periods7, 8 with the strongest correlation being observed between A1C and mean plasma glucose levels. However, the glycemic disorders in type 2 diabetes are not solely limited to sustained chronic hyperglycemia but can be extended to the glycemic variability that includes both upward and downward acute glucose changes.Glycemic variability (GV) means swings in blood glucose level. Diminished or absent glycemic auto regulation or short falls of insulin availability are hypothesized to be the etiological factors for these glycemic bumps. Intermittent high blood glucose exposure rather than constant high blood glucose exposure has been shown to have deleterious effect in experimental studies9,10,11,

12,13. Glycemic variability has been independently linked to cardiovascular and cerebrovascular damage, and about 40% of people who have well-controlled A1Cs still experience frequent high blood glucose episodes throughout the day

Physicians in their day to day practice, utilize quantitative values of glucose parameters such as fasting,

postprandial blood glucose, and glycated hemoglobin (HbA1C). In present era of targeting optimum glycemic control, it is also important to focus on GV as an additional goal point along with the traditionally followed parameters. In the event of new therapeutics in the management of type 2 diabetes mellitus by glucagon like peptide-1 (GLP-1) analogs, SGLT2 Inhibitors and dihydropeptidyl peptidase-IV (DPP-IV) inhibitors through incretin mimetic effect, studying GV in an individual to achieve glycemic control is promising.

The broad definition of GV takes into account the intraday glycemic excursions including episodes of hyper and hypoglycemia. The postprandial hyperglycemic excursions also contribute to GV. The occurrence of various microvascular and macrovascular complications in diabetes is attributed by various studies to hyperglycemia and dysglycemia (peaks and nadirs)14,

15,16,17,18. Several studies have reported that low glucose variability coincided with decreased occurrence of hypoglycaemia19. Glucose variability was mentioned as measure of predictor of future severe hypoglycemia than HbA1c by Cox et al.20 In a study by Kilpatrick et al. using datasets of the DCCT found that glucose variability, calculated as SD of SMB and MAGE was independently predictive of hypoglycemia just like MBG and other study. Diabetes outcomes in veterans study (DOVES) also found the association of risk of hypoglycemia as much related to glucose variability as to the mean glucose value.21,22 Limiting glycemic excursions at the same time maintaining the MBG and HbA1c in target range can be a tool in achieving glycemic control. The relationship of GV was more significant with neuropathy rather than other complications like nephropathy and retinopathy. Furthermore associations were seen with painful neuropathy23 DCCT data showed that pre- and postprandial blood glucose, MBG were significantly related to cardiovascular disease (CVD) risk. However, there was no relation between HbA1c and glucose variability. GV was positively associated with changes in systolic and diastolic blood pressure24,25. In multivariate analyses, glucose peak was a significant independent determinant of carotid intima-media thickness (CIMT) and explained 49% of the variability 26. In a recent study of type 2 diabetes mellitus with stroke, post prandial blood glucose (PPBG) was significantly associated with CIMT and stroke27.

Glucose variability can be regulated by various means. Diet-induced weight loss can significantly improve not only insulin sensitivity but also β-cell function, capable of reducing glucose levels and also reduces Glycemic variability. Recently a research study on diet of high glycemic meal with pistachio nuts has shown blunted postprandial response. Using continuous interstitial glucose sensor monitoring

1Professor, Department of Physiology, KGMU 2Professor, Dept. of Medicine, BBDU, Lucknow

Glycemic Variability and its Clinical ImplicationsDr. Narsingh Verma1 and Dr. Anuj Maheshwari2

Review Article



system (CGMS) measures of glucose intraday variability, MAGE, SD, mean glucose levels, CONGA and inter-day variability, MODD were found to be significantly reduced when treated with acarbose in a 16 week intention-to- treat study with glibenclamide in combination with metformin although the overall glucose level did not differ between the two28. It was observed that medications such as acarbose that target postprandial hyperglycemia not only attenuate glycemic excursions but also reduce oxidative stress and potentially improve endothelial dysfunction. Bao et al. showed that controlled-release glipizide combined with acarbose was more effective in reducing MAGE than controlled-release glipizide monotherapy. Glimepiride logically should cause less GV than glibenclamide. Extra pancreatic effect, rapid association, and dissociation binding properties with receptors and effect on both phases of insulin secretion in patients with type 2 diabetes are the possible mechanisms29,30 The insulin-releasing activity is high with glibenclamide and lowest with glimeperide.30 There is attenuation and progressive delay of prandial insulin response contributing to increasing hyperglycemia in established T2DM. An important consequence of this derangement is that hepatic glucose production is no longer suppressed during times of prandial glucose intake leading to hyperglycemic excursions. Over and above due to longer duration of action, inter meal hypoglycemia is quite common with regular insulin. Newer rapid prandial insulin analogs are rapidly absorbed and their action closely mimics the normal physiological insulin response to meals. Prandial dosage allows to be adjusted on the premeal blood glucose concentration and the estimated carbohydrate content of the meal, using a predetermined correction factor for treating elevated glucose levels and an insulin-carbohydrate ratio to match the insulin dose to the carbohydrate load. In ‘The Treat-to-Target Trial’ addition of long acting basal insulin glargine at bed time in comparison to neutral protamine hagedorn ( NPH) insulin in a poorly controlled on oral agents in overweight randomized type 2 diabetic patients seeking a target fetal bovine serum (FBS) ≤100 mg/dl, had better glycemic control with lesser episodes of hypoglycaemia. It was attributed to better GV in the glargine group. The 8-point self monitored glucose profile showed less within subject variability of FBG. In an another study LANMET the mean A1c level dropped by 2% from base line to end point, it was commented by Monnier et al., that glucose variability remained unchanged, and addition of a bed time insulin dose failed to modify the acute glucose fluctuations from peaks to nadirs, whatever the type of insulin used.An alternative to basal bolus insulin therapy to provide constant 24 h base line insulin and covering meal time glycemic excursions as mentioned above, near mimicking to endogenous insulin availability with premixed 50/50 mealtime plus metformin in type 2 diabetes patients who were on 0-2 insulin injections per day were studied by Robbins et al. The overall HbA1c levels and preprandial blood glucose

and PPBG were lower (except FBG) with similar reduction in nocturnal hypoglycemia and less GV, compared with Glargine and Metformin. With more use of CGM system GV was more evident in patients with similar HbA1c levels. (CSII) Continuous Subcutaneous Insulin Infusion was considered as alternative when glycemic control was not achieved with use of multiple dose insulin regimens in Type 1 diabetic patients. Use of CGM itself in self management in T1DM has been found to have reduced MAGE by 10%, SD, hyperglycemic time, hypoglycemic time, and significant effect on QoL. Chimenti et al. observed that improvement of glycemic control after CSII was associated with reduction in SD, mean glucose, duration, and magnitude of hyperglycemic excursions with no changes in the fasting night period or in duration or magnitude of the hypoglycemic excursions. Glucose-dependent insulinotropic peptide (GIP) and GLP-1 activation of incretin receptors on β-cells increases insulin release in response to glucose and has additional benefits of enhanced glucose disposal in peripheral tissues and protection against ischemia/reperfusion injury. In critical care setting, glucose variability is a predictor of mortality and was set as important goals in glucose management in intensive care unit (ICU). MAGE a measurement of GV was found to be lower in patients receiving exenatide in severely burned pediatric patients and resulted in a reduced amount of exogenous insulin. In another study, Exenatide in comparison with insulin glargine had better postprandial glucose profile and significant reduction in ADRR, a sensitive predictor of either hyper-hypoglycemia despite similar reductions in A1C. Exenatide had better effect on reducing GV when compared with glimerpiride treatment. The benefits imparted by exenatide could be explained by glucose dependent stimulation of insulin secretion and concomitant suppression of glucagons.31 DPP-IV inhibitors increase endogenous GIP and GLP-1 by inhibiting their degradation. Sitagliptin significantly reduced blood 2 and 24 h AUC (Area under curve), MBG, and reduction in time spent in euglycemic range in adult patients with T1DM32. Over and above standard glycemic parameters like blood glucose and glycated hemoglobin, GV can be a future target parameter for optimum glycemic control. This could be applicable to all T1DM, T2DM, gestational diabetes, and probably nondiabetic critically ill patients. Studies have shown improved outcomes for micro and to some extent macrovascular diabetic complications by minimizing GV. In spite of various formulas offered, simple and standard clinical tool to define GV is yet to evolve. Current diabetes medicines like incretin mimetics, newer basal and prandial insulins, CSII and modern bariatric surgical techniques in obese type 2 diabetic patients significantly reduce GV. Still an important question remains to be answered is about the target of GV .



References1. Kannel, W.B. and Mc Gee, D.L. (1979), “Diabetes and

Cardiovascular Diseases: The Framingham Study”, JAMA, Vol. 241, pp. 2035–2038.

2. Laakso, L. and Lehto, S. (1997), “Epidemiology of Macrovascular Disease in Diabetes”, Diabetes Rev., Vol. 5, pp. 294–315.

3. “Diabetes Control and Complications Trial Research Group: The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-term Complications in Insulin-dependent Diabetes Mellitus”, N. Engl. J. Med., Vol. 329, pp. 977–986.

4. Stratton, I.M., Adler, A.I., Neil, H.A., Matthews, D.R., Manley, S.E., Cull, C.A., Hadden, D., Turner, R.C. and Holman, R.R. (2000), “Association of Glycaemia with Macrovascular and Microvascular Complications of Type 2 Diabetes (UKPDS 35), Prospective Observational Study”, BMJ, Vol. 321, pp. 405–412.

5. Brownlee, M. (2001), “Biochemistry and Molecular Cell Biology of Diabetic Complications”, Nature, Vol. 414, pp. 813–820.

6. Brownlee, M. Banting Lecture 2004 (2005), “The Pathobiology of Diabetic Complications: A Unifying Mechanism”, Diabetes, Vol. 54, pp. 1615–1625.

7. Avignon, A., Radauceanu, A. and Monnier, L. (1997), “Nonfasting Plasma Glucose is a Better Marker of Diabetic Control than Fasting Plasma Glucose in Type 2 Diabetes”, Diabetes Care, Vol. 20, pp. 1822–1826.

8. Kebbi, I.M., Ziemer, D.C., Cook, C.B., Gallina, D.L., Barnes, C.S. and Philipps, L.S. (2004), “Utility of Casual Postprandial Glucose Levels in Type 2 Diabetes Management”, Diabetes Care, Vol. 27, pp. 335–339.

9. Quagliaro, L., Piconi, L., Assaloni, R., Martinelli, Motz, E. and Ceriello, A. (2003), “Intermittent High Glucose Enhances Apoptosis Related to Oxidative Stress in Human Umblical Vein Endothelial Cells: The Role of Protein Kinase C and NAD(P) H-oxidase Activation”, Diabetes, Vol. 52, pp. 2795-804.

10. Piconi, L., Quagliaro, L., Assaloni, R., Da Ros, R., Maier, A. and Zuodar, G. et al. (2006), “Constant and Intermittent High Glucose Enhances Endothelial Cell Apoptosis Through Mitochondrial Superoxide Overproduction”, Diabetes Metab Res. Rev., Vol. 22, pp. 198-203.

11. Takeuchi, A., Throckmorton, D.C., Brogen, A.P., Yoshizawa, N., Rasmussen, H. and Kashgarian, M. (1995), “Periodic High Extra Cellular Glucose Enhances Production of Collagens III and IV by Mesangial Cells”, Am. J. Physiol., Vol. 268(1 Pt 2), pp. F13-9

12. Jones, S.C., Saunders, H.J., Qi, W. and Pollock, C.A. (1999), “Intermittent High Glucose Enhances Cell Growth and Collagen Synthesis in Cultured Human Tubulointerstitial Cells”, Diabetologia, Vol. 42, pp. 1113–9.

13. Hovath, E.M., Benko, R., Kiss, L., Muranyi, M., Pek, T. and Fekete, K. et al. (2009), “Rapid Glycaemic Swings Induce Oxidative Stress, Activate Poly-(ADP-ribose) Polymerase and Impair Endothelial Function in a Rat Model of Diabetes Mellitus”, Diabetologia, Vol. 52, pp. 952–61.

14. Stratton, I.M., Adler, A.I., Neil, H.A., Mathews, D.R., Manley, S.E. and Cull, C.A. et al. (2000), “Association of Glycaemia with Macrovascular and Microvascular Complications of Type 2 Diabets (UKPDS 35): Prospective Observational Study”, BMJ., Vol. 321, pp. 405–12.

15. Raz, I., Wilson, P.W., Strojek, K., Kowalska, I., Bozikov, V. and Gitt, A.K. et al. (2009), “Effects of Prandial Versus Fasting Glycemia on Cardiovascular Outcomes in Type 2 Diabetes: The HEART 2D Trial”, Diabetes Care, Vol. 32, pp. 381–6.

16. Kota, S.K., Kota, S.K., Jammula, S., Panda, S. and Modi, K.D. (2011), “Effect of Diabetes on Alteration of Metabolism in Cardiac Myocytes: Therapeutic Implications”, Diabetes Technol Ther., Vol. 13, pp. 1155–60.

17. Kota, S.K., Meher, L.K., Jammula, S., Kota, S.K., Krishna, S.V. and Modi, K.D. (2012), “Aberrant Angiogenesis: The Gateway to Diabetic Complications”, Indian J. Endocrinol. Metab, Vol. 16, pp. 918–30.

18. Kumar, Hari K.V., Kota, S.K., Basile, A. and Modi, K.D. (2012), “Profile of Microvascular Disease in Type 2 Diabetes in a Tertiary Health Care Hospital in India”, Ann Med. Health Sci. Res., Vol. 2, pp. 103-8.

19. Jeha, G.S., Karaviti, L.P., Anderson, B., Smith, E.O., Donaldson, S. and McGirk, T.S. et al. (2005), “Insulin Pump Therapy in Preschool Children with Type 1 Diabetes Mellitus Improves Glycemic Control and Decreases Glucose Excursions and the Risk of Hypoglycemia”, Diabetes Technol Ther., Vol. 7, pp. 876–84.

20. Cox, D.J., Kovatchev, B.P., Julian, D.M., Gonder-Frederick, L.A., Polonsky, W.H. and Schlundt, D.G. et al. (1994), “Frequency of Severe Hypoglycemia in Insulin-dependent Diabetes Mellitus can be Predicted from Self-monitoring Blood Glucose Data”, J. Clin. Endocrinol. Metab, Vol. 79, pp. 1659–62.

21. Murata, G.H., Hoffman, R.M., Shah, J.H., Wendel, C.S. and Duckworth, W.C. (2004), “A Probabilistic Model for Predicting Hypoglycemia in Type 2 Diabetes Mellitus: The Diabetes Outcomes in Veterans Study (DOVES)”, Arch. Intern. Med., Vol. 164, pp. 1445–50.

22. Kilpatrick, E.S., Rigby, A.S., Goode, K. and Atkin, S.L. (2007), “Relating Mean Blood Glucose and Glucose Variability to the Risk of Multiple Episodes of Hypoglycaemia in Type 1 Diabetes”, Diabetologia, Vol. 50, pp. 2553–61.

23. Oyibo, S.O., Prasad, Y.D., Jackson, N.J., Jude, E.B. and Boulton, A.J. (2002), “The Relationship Between Blood Glucose Excursions and Painful Diabetic Peripheral Neuropathy: A Pilot Study”, Diabet. Med., Vol. 19, pp. 870-3.

24. Kilpatrick, E.S., Rigby, A.S. and Atkin, S.L. (2008), “Mean Blood Glucose Compared with HbA1c in the Prediction of Cardiovascular Disease in Patients with Type 1 Diabetes”, Diabetologia, Vol. 51, pp. 365-71.

25. Gordin, D., Rönnback, M., Forsblom, C., Mäkinen, V., Saraheimo, M. and Groop, P.H. (2008), “Glucose Variability, Blood Pressure and Arterial Stiffness in Type 1 Diabetes”, Diabetes Res. Clin. Pract., Vol. 80, pp. e4–7.

26. Esposito, K., Giugliano, D., Nappo, F. and Marfella, R. (2004), “Campanian Postprandial Hyperglycemia Study Group, Regression of Carotid Atherosclerosis by Control of Postprandial Hyperglycemia in Type 2 Diabetes Mellitus”, Circulation, Vol. 110, pp. 214–9.

27. Kota, S.K., Mahapatra, G.B., Kota, S.K., Naveed, S., Tripathy, P.R. and Jammula, S. et al., Carotid Intima Media Thickness in Type-2 Diabetes Mellitus with Ischemic Stroke”, Indian J. Endocrinol Metab (In press).



28. Lin, S.D., Wang, J.S., Hsu, S.R., Sheu, W.H., Tu, S.T. and Lee, I.T. et al. (2011), “The Beneficial Effect of Alpha-glucosidase Inhibitor on Glucose Variability Compared with Sulfonylurea in Taiwanese Type 2 Diabetic Patients Inadequately Controlled with Metformin: Preliminary Data”, J. Diabetes Complications, Vol. 25, pp. 332–8.

29. Davis, S.N. (2004), “The Role of Glimepiride in the Effective Management of Type 2 Diabetes”, J. Diabetes Complications, Vol. 18, pp. 367–76.

30. Muller, G., Satho, Y. and Geisen, K. (1995), “Extrapancreatic Effects of Sulfonylureas-A Comparison Between Glimepiride and Conventional Sulfonylureas”, Diabetes Res. Clin. Pract., Vol. 28, pp. S115–3.

31. Muller, G., Satho, Y. and Geisen, K. (1995), “Extrapancreatic Effects of Sulfonylureas-A Comparison Between Glimepiride and Conventional Sulfonylureas”, Diabetes Res. Clin. Pract., Vol. 28, pp. S115–37.

32. Irace, C., Fiorentino, R., Carallo, C., Scavelli, F. and Gnasso, A. (2011), “Exenatide Improves Glycemic Variability Assessed by Continuous Glucose Monitoring in Subjects with Type 2 Diabetes”, Diabetes Technol. Ther., Vol. 13, pp. 1261–3.

33. Ellis, S.L., Moser, E.G., Snell-Bergeon, J.K., Rodionova, A.S., Hazenfield, R.M. and Garg, S.K. (2011), “Effect of Sitagliptin on Glucose Control in Adult Patients with Type 1 Diabetes: A Pilot, Double-blind, Randomized, Cross Over Trial”, Diabet Med., Vol. 28, pp. 1176–81.



Prevalence and Natural History

Fibromuscular dysplasia is a collection of vascular diseases that affects the intima, media, and adventitia

(periarterial fibromuscular dysplasia). Fibromuscular dysplasia accounts for less than 10 percent of cases of renal-artery stenosis, and 90 percent of cases of fibromuscular dysplasia involve the media. It tends to affect girls and women between 15 and 50 years of age, frequently involves the distal two thirds of the renal artery and its branches, and is characterized by a beaded, aneurysmal appearance on angiography. It rarely leads to renal-artery occlusion. The cause of fibromuscular dysplasia is unknown, although many theories have been advanced, including those involving a genetic predisposition, smoking, hormonal factors, and disorders of the vasa vasorum as risk factors.

Atherosclerosis accounts for 90 percent of cases of renal-artery stenosis and usually involves the ostium and proximal third of the main renal artery and the perirenal aorta. In advanced cases, segmental and diffuse intrarenal atherosclerosis may also be observed, particularly in patients with ischemic nephropathy. The prevalence of atherosclerotic renal-artery stenosis increases with age, particularly in patients with diabetes, aortoiliac occlusive disease, coronary artery disease, or hypertension.1,2 Among patients with atherosclerotic renal-artery stenosis, progressive stenosis was reported in 51 percent of renal arteries five years after diagnosis (including 18 percent

of initially normal vessels),3 only 3 to 16 percent of renal arteries became totally occluded,1,3 and renal atrophy developed in 21 percent of patients with renal-artery stenosis of more than 60 percent. Thus, atherosclerotic renal-artery stenosis is a common and progressive disease, particularly in patients with diabetes mellitus or other manifestations of atherosclerosis. Nevertheless, it is likely that many cases of atherosclerotic renal-artery stenosis are never detected because refractory hypertension or renal failure does not develop.

Renal-Artery Stenosis and HypertensionA decrease in renal perfusion pressure activates the renin–angiotensin system, which leads to the release of renin and the production of angiotensin II; has direct effects on sodium excretion, sympathetic nerve activity, intrarenal prostaglandin concentrations, and nitric oxide production; and causes renovascular hypertension.4,5 When hypertension is sustained, plasma renin activity decreases (referred to as “reverse tachyphylaxis”).

Although renovascular hypertension often contributes to accelerated or malignant hypertension, it is not readily distinguishable from essential hypertension. Certain classic features, such as hypokalemia, an abdominal bruit, the absence of a family history of essential hypertension, a duration of hypertension of less than one year, and the onset of hypertension before the age of 50 years, are more suggestive of renovascular hypertension than of other types of hypertension,6 but none have strong predictive value. In fact, the majority of patients with renal-artery stenosis who have hypertension have essential hypertension, as suggested by the fact that the hypertension usually persists despite successful revascularization.

Noninvasive EvaluationPatients with certain clinical features associated with renal-artery stenosis are often considered for further

1MD, DM, FCCP, FCSI, Senior Interventional Cardiologist,Metro Hospitals & Heart Institute, Noida2MD, AB (USA), FACC, FRCP(C), MBCIS, FSCAI (USA),Director Interventional Cardiology, Metro Hospitals & Heart Institute, Noida

Renal Artery Stenosis—An UpdateDr. Prashant T. Upasani1 and Dr. Purshotam Lal2

ABSTRACTRenal artery stenosis is of varying etiology. Common causes include fibromuscular dysplasia and atherosclerotic narrowing of renal arteries. It commonly leads to hypertension and/or renal failure; however, quite often it is never detected. Activation of renin-angiotensin system place a role in development of hypertension. A variety of noninvasive test are available to diagnose renal artery stenosis. It can also be detected by invasive method such as contrast-enhanced angiography. Renal artery stenosis is treated by a combination of medical therapy especially angiotensin converting enzyme inhibitors or angiotensin-receptor blockers. Goals of treatment include preservation of renal function, improved control of hypertension and prevention of dialysis. Surgical revascularization has fallen out of place and has given way to percutaneous intervention namely balloon angioplasty with or without stenting. Hypertension is often “cured” following revascularization procedures especially in patient with fibromuscular dysplasia than in those with atherosclerotic renal artery stenosis. Long-term results are better in patients who have preserved renal function at baseline.Primary diseases of the renal arteries often involve the large renal arteries, whereas secondary diseases are frequently characterized by small vessel and intrarenal vascular disease. Renal artery stenosis may occur alone (isolated anatomical renal-artery stenosis) or in association with hypertension, renal insufficiency (ischemic nephropathy), or both.

Review Article



evaluation (Table 1). The evaluation may include studies to assess overall renal function, physiological studies to assess the renin–angiotensin system, perfusion studies to assess differential renal blood flow, and imaging studies to identify renal-artery stenosis (Table 2). Methods of measuring the response of the renin–angiotensin system include renin-sodium profiling, assessment of plasma renin activity before and after the administration of captopril, assessment of the effect on blood pressure and renal function of an angiotensinconverting–enzyme (ACE) inhibitor, and captopril renography to assess differential renal perfusion. The tests are not recommended in most elderly patients with atherosclerotic renal-artery stenosis and hypertension, since hypertension in these patients is not rennin dependent and the results do not reliably predict the course of hypertension after revascularization. In contrast, these studies are more useful for identifying patients with fibromuscular dysplasia in whom hypertension is likely to be cured by revascularization, since this disorder is frequently renin-dependent.7,8

Table 1. Clinical Findings Associated with Renal–Artery Stenosis

HypertensionAbrupt onset of hypertension before the age of 50 years (suggestive of fibromuscular dysplasia)Abrupt onset of hypertension at or after the age of 50 years (suggestive of atherosclerotic renal-artery stenosis)Accelerated or malignant hypertension

Refractory Hypertension (not responsive to therapy with »3 drugs)Renal Abnormalities

Unexplained azotemia (suggestive of atherosclerotic renal-artery stenosis)Azotemia induced by treatment with an angiotensin-converting–enzyme inhibitorUnilateral small kidneyUnexplained hypokalemia

Other FindingsAbdominal bruit, flank bruit, or bothSevere retinopathyCarotid, coronary, or peripheral vascular diseaseUnexplained congestive heart failure or acute pulmonary edema

Table 2: Noninvasive Assessment of Renal Artery Stenosis

Study Rationale Strengths LimitationsPhysiological studies to assess the renin–angiotensin system

Measurement of peripheral plasma rennin Activity

Measurement of captopril-stimulated rennin-Activity

Measurement of renal-vein rennin- activity

Functional studies to assess overall renal function

Measurement of serum creatinine

Urinalysis

Nuclear imaging with [ 125I]iothalamate or chromium Cr 51–labeled pentetic acid (DTPA) to determine the glomerular filtration rate

Perfusion studies to assess differentialrenal blood flow

Captopril renography with technetium99m Tc mertiatide (99mTc MAG3)

Nuclear imaging with technetium mertiatide or technetium-labeled pentetic acid (DTPA) to estimate fractional flow to each kidney

Vascular studies to evaluate the renalarteriesDuplex ultrasonography

Magnetic resonance angiography

Computed tomographic angiography

Reflects the adequacy of sodiumexcretion

Produces a fall in pressure distalto the stenosis

Compares renin release fromthe two kidneys

Measures overall renal function

Assesses urinary sediment andproteinuria

Measures overall glomerularfiltration rate

Captopril-mediated fall in filtration pressure amplifiesdifferences in renal perfusion

Estimates fractional flow toeach kidney

Shows the renal arteries andmeasures flow velocity as ameans of assessing the severityof stenosis

Shows the renal arteries andperirenal aorta

Shows the renal arteries andperirenal aorta

Measures the level of activationof the renin–angiotensin system

Enhances the release of reninfrom the stenotic kidney

Lateralization predictive ofimprovement in blood pressurewith revascularization

Readily available; inexpensive

Readily available; inexpensive

Useful for estimating glomerularfiltration rate in patients with normal and abnormal renal function

Normal study excludes renovascular hypertension

Allows calculation of single kidney glomerular filtrationrate

Inexpensive; widely available

Not nephrotoxic; useful in patients with renal failure; provides excellent images

Provides excellent images; stents do not cause artifacts

Low predictive accuracy for renovascular hypertension; results influenced by medications and many other conditionsLow predictive accuracy for renovascular hypertension; results influenced by many other conditions

Nonlateralization not predictive of thefailure of blood pressure to improvewith revascularization; results influenced by medications and many other conditions

Not sensitive to early changes in renalmass or single-kidney function

Results are nonspecific and influenced by many other diseases

Expensive; not widely available

Multiple limitations in patients with advanced atherosclerosis or creatinine>2.0 mg/dl (177 µmol/liter)

Results may be influenced by the presence of obstructive uropathy

Heavily dependent on operator’s experience; less useful than invasive angiography for the diagnosis of fibromuscular dysplasia and abnormalities in accessory renal arteries

Expensive; less useful than invasive angiography for the diagnosis of fibromuscular dysplasia; stents result in imaging artifacts

Not widely available; the large volume of contrast medium required is potentially nephrotoxic



Because of the limited usefulness of physiological studies in elderly patients with atherosclerotic renal artery stenosis, imaging techniques are preferable as a means to identify stenosis in such patients. Duplex ultrasonography can provide images of the renal arteries and assess blood-flow velocity and pressure waveforms, but there is a 10 to 20 percent rate of failure due to the operator’s inexperience or the presence of obesity or bowel gas.9 Gadolinium-enhanced magnetic resonance angiography and computed tomographic angiography are useful for evaluating the renal circulation and aorta, but they are less reliable for visualizing distal segments and small accessory arteries.10 Gadolinium is not nephrotoxic and is useful in patients with renal insufficiency.

Invasive EvaluationThe goals of contrast-enhanced angiography are to confirm the diagnosis and cause of renal-artery stenosis and to evaluate the extent of intrarenal vascular disease, determine the dimensions of the kidneys, and identify associated aneurysmal or occlusive diseases of the aorta. Low-osmolar contrast material is recommended to minimize the discomfort of injections of contrast mediums, but it must be used cautiously in patients with renal failure because of its nephrotoxicity. Intraarterial digital subtraction techniques may reduce the volume of contrast medium needed to 15 to 20 ml, an amount that would not be expected to lead to worsening of base-line renal function in most patients. In patients with advanced oliguric renal failure, the use of noniodinated contrast agents such as carbon dioxide or gadolinium may obviate the risk of contrast medium–induced nephropathy.

Medical TherapyPatients with fibromuscular dysplasia rarely have excretory dysfunction, and hypertension in these patients generally responds to ACE inhibitors or - in patients with refractory hypertension–to renal angioplasty. For patients with hypertension and atherosclerotic renal-artery stenosis, aspirin, cholesterol-lowering drugs, and smoking cessation are essential to limit atherosclerosis. ACE inhibitors and angiotensin-receptor blockers are effective in 86 to 92 percent of these patients,11 but the loss of renal mass and reduction in transcapillary filtration pressure can produce acute or chronic renal insufficiency, especially if renal-artery stenosis affects both kidneys or the sole functional kidney.12 ACE-inhibitor–induced renal insufficiency is potentiated by sodium depletion and preexisting renal dysfunction, is usually reversible if detected promptly, and often provides an indication that critical renovascular disease is present. When the serum creatinine concentration is normal, potential loss of renal mass can be predicted on the basis of the finding on nuclear imaging that fractional flow to the stenotic kidney is impaired (Table 2), and this finding may provide further justification for renal revascularization.1,13,14

The goals of treatment, both surgical and percutaneous for renal artery stenosis include preservation of renal

function, improved control of hypertension, and prevention of haemodialysis. Improvement in blood pressure control and reduction in the number of antihypertensive medications is common, but complete resolution of hypertension is unusual because concomitant essential hypertension often coexists. To the extent that severe renal artery disease can cause renal dysfunction, the identification and treatment of functionally significant renal artery stenosis could have major health benefits. A major question remaining is whether percutaneous renal revascularisation can slow, delay, or prevent deterioration in renal function and subsequent haemodialysis.

Surgical RevascularizationBefore ACE inhibitors and balloon angioplasty became available, unilateral aortorenal bypass surgery was the most common surgical technique.15 The use of aortorenal bypass has declined in many centers, and extra-anatomical bypass (in which the bypass originates from the celiac or mesenteric branches rather than the aorta) now accounts for 80 percent of renal bypass operations in some centers.15,16 Perioperative mortality rates range from 2.1 percent to 6.1 percent for extraanatomical bypass15 and from 1 percent to 4.7 per-cent for renal endarterectomy.17,18 Factors that increase perioperative mortality include the need for aortic reconstruction, the presence of severe preoperative azotemia, the need for bilateral renal bypass, and the use of an aortic graft as the source of aortorenal bypass. Independent predictors of an increased likelihood of death in the perioperative period include early graft failure, the presence of coronary artery disease, the presence of uncontrolled hypertension, and the need for abdominal aortic-aneurysm repair.17 Other complications include myocardial infarction (in 2.0 to 9.0 percent of patients),15,18 stroke (in 0 to 3.3 percent),16 hemorrhage requiring surgical exploration (in 2.0 to 3.0 percent),19 and cholesterol embolization (in 1.0 to 4.3 percent).14,16

Early graft failure has been reported in 1.4 to 10 percent of patients,16,19 is usually due to graft thrombosis associated with technical problems, and is the strongest independent predictor of perioperative death.17 In contrast, late graft failure is usually due to the presence of organized thrombus, intimal proliferation, and progressive atherosclerosis. At five years, the rate of graft failure ranges from 6 percent to 18 percent,17,20,21 repeated operation or angioplasty is required in 5 to 15 percent of patients,15 and the survival rate is 65 to 81 percent.15,20,22 Independent predictors of increased late mortality include an age of more than 70 years at the time of the bypass, the presence of coronary artery disease, and preoperative uncontrolled hypertension.17,21 Follow-up imaging studies are recommended after revascularization, particularly if conditions suggesting graft failure, such as hypertension or renal dysfunction, develop.



Percutaneous InterventionPercutaneous revascularization of renal-artery stenosis involves conventional balloon angioplasty, with or without stenting. Guiding-catheter techniques are commonly employed, which involve the use of coronary or peripheral guide wires and balloon catheters. Although anatomical revascularisation may allow improved antihypertensive management and preserve renal parenchymal function, how does percutaneous therapy compare to surgery? This question is particular importance, given the advanced age of many patients with atherosclerotic disease and the significant perioperative morbidity and operative mortality rates of upto 6 percent associated with surgical therapy. Only one randomized, controlled study has compared surgical therapy versus balloon angioplasty for unilateral atherosclerotic renal artery stenosis.23 The author reported slightly lower primary patency rates in the balloon angioplasty group, as one may expect in the prestent era. However, secondary patency was 90 percent in the angioplasty group and 97 percent in the surgical group with comparable improvement in blood pressure and similar likelihood of improvement or stabilization in renal function after intervention. Even in the prestent era, the results of percutaneous intervention compared favourably to those of surgery.24,25

Conventional balloon angioplasty is considered the treatment of choice for patients with uncontrolled hypertension and fibromuscular dysplasia. The procedure is successful in 82 to 100 percent of patients,26 and stenosis recurs in 10 to 11 percent.27 In contrast, conventional balloon angioplasty is less effective for atherosclerotic renal-artery stenosis,27 because of the potential for dissection and the elastic recoil and rigidity of the lesions.28 These limitations account for the incidence of restenosis of 10 to 47 percent after renal angioplasty. An analysis of the pooled results of studies of conventional balloon angioplasty in 1118 patients showed that 0.5 percent died in the hospital, 0.3 percent underwent nephrectomy, 2.0 percent required renal surgery,26 2.2 percent had occlusion of a side branch of the renal artery, 1.1 percent had cholesterol embolization, and 2.3 percent sustained an injury at the site of vascular access.26 The rate of immediate success of conventional balloon angioplasty is higher for nonostial atherosclerotic renal-artery stenosis (72 to 82 percent) than for ostial atherosclerotic renal-artery stenosis (60 to 62 percent).29 As compared with patients with fibromuscular dysplasia, patients with atherosclerotic renal-artery stenosis have much lower rates of event-free survival29 and late vessel patency.30

Stenting is an attractive alternative to conventional balloon angioplasty for atherosclerotic renal-artery stenosis, because of its efficacy in resolving dissections, elastic recoil, residual stenoses, and translesional pressure gradients after conventional balloon angioplasty.31

Percutaneous Transluminal Balloon Angioplasty versus Medical TherapyA meta-analysis32 comparing balloon angioplasty versus medical therapy alone in the three mentioned trials, comprising a total of 210 patients with at least 50 percent stenosis in unilateral/bilateral RAS and poorly controlled hypertension, described a modest improvement of systolic and diastolic blood pressure and need for fewer antihypertensive medications in favor of angioplasty. There was no consistent difference in changes in renal function between the group treated with angioplasty and the group receiving medical therapy alone. Patency of the renal arteries after 12 months was more likely in the angioplasty group. A more recent study revealed that the modest decrease in antihypertensive medication did not have an impact in terms of quality of life improvement.33

Percutaneous Transluminal Balloon Angioplasty versus Renal Artery Stent PlacementA meta-analysis34 of renal arterial stent placement and renal percutaneous transluminal balloon angioplasty studies performed until 1998, including a total of 1322 patients, revealed that stenting was technically superior and clinically comparable to balloon angioplasty alone. Stent placement had a higher technical success rate and a lower restenosis rate than did renal percutaneous angioplasty (98 percent vs. 77 percent and 17 percent vs. 26 percent, respectively; P<.001). The improvement rate for renal function was lower after stent placement than after percutaneous angioplasty (20 percent vs. 10 percent and 30 percent vs. 38 percent respectively; P<.001).

A more recent multicenter randomnized prospective trial compared balloon angioplasty alone versus balloon angioplasty with stent implantation in patients (n=84) with ostial renal artery stenosis. The primary success rate of balloon angioplasty was 57 percent, compared with 88 percent for stenting. Complications were similar. At 6 months, the primary patency rate was 29 percent for balloon angioplasty and 75 percent for stenting. Restenosis after a successful primary procedure occurred in 48 percent of patients for balloon angioplasty and 14 percent for stenting. Patients who underwent secondary stenting for primary or late failure of balloon angioplasty within the follow-up period had a success rate similar to that of primary stenting. Primary stenting was better than balloon angioplasty to achieve vessel patency in ostial atherosclerotic renal artery stenosis. Primary stenting and primary balloon angioplasty plus rescue stenting had similar clinical outcomes at 6 months (intension-to-treat analysis). However, the burden of repeat intervention after balloon angioplasty outweighed the potential savings of the cost of the stent in the original procedure.35

The renal function response seemed difficult to predict in these trials, and improvement, stabilization, or worsening each occurred in one third of patients. Certain subgroups seemed more prone to respond



with improvement of stabilization, such as nondiabetic patients with bilateral stenosis. A prospective trial that included 215 patients with ostial renal artery stenosis of 70 percent or greater treated with stent supported angioplasty identified the following independent predictors of improved renal function: baseline serum creatinine and left ventricular function.36 Female gender, elevated baseline mean blood pressure, and normal renal parenchymal thickness were independent predictors for decrease mean blood pressure after stenting.36 However, other prospective trials did not find any independent predictors of improved renal function.37

Despite the potential benefits, it is unclear whether angioplasty plus stent placement preserves renal function or slows the deterioration of renal function over time. The assumed correlation between angiographic improvement, lower restenosis rates, and enhanced long-term renal function has not been clearly proven.

Bare Metal versus Drug-Eluting Renal Artery Stent PlacementRestenosis rates after bare metal stenting of the renal arteries vary between 6 percent and 20 percent, depending significantly on the definition of restenosis. The renal artery diameter and the stent diameter are independent predictors of in-stent restenosis. Renal arteries with a diameter of 5 mm or less are particularly at risk, with a rate of restenosis of 20 percent or more.38 Therefore, it is hypothesized that patients with small renal arteries might benefit with a lower restenosis rate from the use of drug-eluting stents.

The GREAT trial39 (Palmaz Genesis peripheral stainless steel balloon-expandable stent: comparing a sirolimus coated vs. bare stent I Renal Artery Treatment) is the only completed study comparing the efficacy of drug-eluting versus bare metal stents in the setting of renal artery angioplasty and stenting. The results show a 50 percent relative risk reduction of angiographic in-stent restenosis (70 percent with sirolimus-eluting stent vs. 14 percent with bare metal stent). The stents used were exclusively 5 mm and 6 mm in diameter.

Drug-eluting stents may have a role in the treatment of small renal arteries, particularly in patients with impaired renal function in whom reintervention would lead to recurrent exposure to contrast agents or embolism. Another indication could be the treatment of in-stent restenosis, which until now has been treated with repeat balloon angioplasty or placement of a bare metal stent within the previously placed stent.

In renal arteries with a diameter of at least 6 mm bare metal stenting should be the treatment of choice, because the rate of restenosis is considered to be low.38

Distal Protection DevicesThe relatively frequent deterioration of renal function despite successful percutaneous renal artery revascularization is theorized to be a result of micro-

embolization of atherothrombotic debris liberated during the percutaneous revascularization procedure. This theory forms the rationale for the use of a distal artery embolic protection devices during percutaneous renal revascularization procedures. No randomized controlled trials have yet been published regarding this theoretical improvement in percutaneous renal revascularization. Several small, noncontrolled studies using different RPDs (filter and occlusion devices) showed lower rates of postprocedure renal function deterioration (50 percent-10 percent at 1-3 month’s follow-up)40,41 than the rates published in the literature regarding renal artery intervention without distal protection. In most of the patients studied (60 percent-80 percent)40,41 the devices successfully removed debris in the form of fresh thrombus, chronic thrombus, atheromatous fragments, and cholesterol clefts. Despite promising initial data, the use of these devices is not currently recommended, and additional investigation is needed before their use would become routine or mandatory.

Effect of Revascularization on HypertensionPublished studies of the outcome of revascularization for renal-artery stenosis have had numerous limitations. Hypertension has been classified as “cured” (i.e., the blood pressure is normal without a need for medication), improved (the number or dose of medications is reduced, blood pressure is better controlled, or both), or unchanged, but the ability to make direct comparisons among studies is limited because of differences in medical therapy, target blood pressure, and criteria for improvement. Interpretation of the data is further limited by the uncertain clinical relevance of these classification groups, since statistically significant differences in blood pressure and medications may not be clinically significant. Finally, the effects on renal-artery stenosis of aggressive lipid-lowering therapy, risk-factor modification, antihypertensive therapy, and aspirin have not been studied. These important limitations may partially explain the lack of enthusiasm of some physicians for further studies of the use of renal angiography and revascularization to control hypertension.

Despite these limitations, it is apparent that hypertension is more likely to be cured after revascularization in patients with fibromuscular dysplasia than in those with atherosclerotic renal-artery stenosis (60 percent vs. <30 percent), regardless of the type of revascularization.13,18,27,29 Recurrent hypertension after initial improvement is unusual,42 but if it occurs, it may be due to restenosis, atherosclerosis, or both. Two small randomized trials of conventional balloon angioplasty and medical therapy demonstrated a significant decrease in blood pressure and a reduced need for medication in the conventional angioplasty group, but cure of hypertension was rare.43,44 A recent randomized trial involving patients with hypertension and atherosclerotic renal-artery stenosis showed no significant difference in outcomes between angioplasty and medical therapy.45 Like other



means of revascularization, stenting has been associated with a small but statistically significant decrease in blood pressure and in the need for medication at four years.46 The rates of cure of hypertension after stenting are low and are similar to those associated with surgery and conventional balloon angioplasty.31

RecommendationsThe evaluation and treatment of patients with renal artery stenosis must be individualized on the basis of clinical factors such as age, existing medical conditions, the likelihood that the correction of renal-artery stenosis will improve blood-pressure control and renal function, and the risk entailed by invasive procedures. Our recommendations are chiefly based on clinical characteristics, an assessment of risk factors for renal-artery stenosis (Table 1), base-line renal function, and the degree of asymmetry in renal blood flow on nuclear imaging (Table 2); the primary goal is to preserve renal function.

The base-line assessment of renal function should include measurement of the serum creatinine concentration and urinalysis. For patients who have no clinical findings suggestive of renal-artery stenosis, we recommend medical therapy, periodic follow-up, and aggressive modification of risk factors for atherosclerosis. Patients who have one or more clinical findings

should be considered for further evaluation. For patients with normal renal function who have at least one clinical finding and who require coronary or peripheral arteriography for other reasons, we recommend abdominal aortography, since it adds little or no risk to the angiographic procedure. For patients with base-line renal insufficiency or those who do not require invasive angiography, we prefer magnetic resonance angiography, because it provides information about the anatomy of renal arteries, kidneys, and aorta. If the results of noninvasive studies suggest the presence of renal-artery stenosis, we recommend nuclear imaging studies to determine the total glomerular filtration rate and the glomerular filtration rate of each kidney. If the patient has unilateral renal-artery stenosis and normal renal function, and the blood flow to both kidneys is symmetric, we recommend continued close follow-up without intervention. Noninvasive vascular imaging or studies of the glomerular filtration rate in each kidney should be repeated periodically to monitor the progression of the disease.

The indications for revascularization of the renal arteries are the subject of controversy. In the presence of unilateral renal-artery stenosis and asymmetric blood flow, or of bilateral renal-artery stenosis, we recommend angiography and revascularization for patients with normal or mildly impaired renal function. In patients with refractory hypertension and renalartery stenosis, the likelihood of cure of hypertension is highest among those with fibromuscular dysplasia, and conventional

balloon angioplasty is the treatment of choice. In patients with atherosclerotic renal-artery stenosis, control of hypertension is facilitated by revascularization, cure of hypertension is unusual, and preservation of renal function may be more important. However, we consider chronic hypertension a weak indication for renal revascularization (because most studies suggest that such an approach has only a small effect on hypertension), unless accelerating or malignant hypertension develops, suggesting the presence of a renovascular component.

The revascularization technique to be used depends on the presence or absence of associated aortoiliac diseases. Stenting is reasonable in cases of unilateral or bilateral atherosclerotic renal-artery stenosis that are not associated with disease of the aorta. For complicated cases involving renal-artery stenosis and aortic aneurysmal or occlusive disease, surgical revascularization and renal bypass are both reasonable approaches. Some surgeons prefer to perform aortic replacement, followed by percutaneous treatment of renal-artery stenosis. Serial studies of the glomerular filtration rate of each kidney and magnetic resonance angiography or duplex ultrasonography should be performed yearly after revascularization to monitor renal perfusion and vessel patency.

For patients with advanced renal dysfunction, revascularization of both renal arteries (or of one in patients with a single functional kidney) may be considered, but the decision to intervene is heavily dependent on the presence of other known renal and extrarenal diseases. We believe that the presence of diabetic nephropathy, severe proteinuria, and poor cortical blood flow would argue against the possibility that the ischemic nephropathy is reversible. The presence of unilateral renal-artery stenosis and severe renal failure indicates advanced parenchymal disease and thus that the risk entailed by revascularization is not justified.

ConclusionAtherosclerotic renal-artery stenosis is a common manifestation of generalized atherosclerosis and is frequently associated with hypertension and excretory dysfunction. However, the association of renal-artery stenosis with hypertension or renal insufficiency does not establish causation, and although the methods for the diagnosis and treatment of renal-artery stenosis have improved, the use of invasive diagnostic techniques and treatment early in the course of the disease still has no proven benefit. Furthermore, there seems to be a shift away from identifying patients with renovascular hypertension, because of the known benefits of medical therapy and the lack of sustained cure after percutaneous or surgical revascularization, and a shift toward identifying patients with renal-artery stenosis who are at risk for excretory dysfunction. Because of this shift, medical therapy and modification of risk factors to limit



atherosclerosis are essential in all patients, regardless of whether they have undergone revascularization. In patients with atherosclerotic renal-artery stenosis who are at risk for excretory dysfunction, percutaneous and surgical techniques may improve or stabilize renal function.

The long-term results are better in patients who have better renal function at base line, suggesting that deferring revascularization until renal function deteriorates may not be the best approach; further study is clearly needed.

References1. Tollefson, D.F. and Ernst, C.B. (1991), “Natural History

of Atherosclerotic Renal Artery Stenosis Associated with Aortic Disease”, J. Vasc. Surg., Vol. 14, pp. 327–31.

2. Crowley, J.J., Santos, R.M. and Peter, R.H. et al. (1998), “Progression of Renal Artery Stenosis in Patients Undergoing Cardiac Catheterization”, Am Heart J., Vol. 136, pp. 913–8.

3. Caps, M.T., Perissinotto, C. and Zierler, R.E. et al. (1998), “Prospective Study of Atherosclerotic Disease Progression in the Renal Artery”, Circulation, Vol. 98, pp. 2866-72.

4. “An Epidemiological Approach to Describing Risk Associated with Blood Pressure Levels: Final Report of the Working Group on Risk and High Blood Pressure”, Hypertension, Vol. 7, pp. 641–51, (1985).

5. Border, W.A. and Noble, N.A. (1998), “Interactions of Transforming Growth Factor Beta and Angiotensin II in Renal Fibrosis”, Hypertension, Vol. 31, pp. 181–8.

6. Simon, N., Franklin, S.S., Bleifer, K.H. and Maxwell, M.H. (1972), “Clinical Characteristics of Renovascular Hypertension”, JAMA, Vol. 220, pp. 1209–18.

7. Oei, H.Y., Geyskes, G.G., Mees, E.J. and Puylaert, C.B. (1987), “The Significance of Captopril Renography in Renovascular Hypertension”, Contrib Nephrol, Vol. 56, pp. 95–103.

8. Setaro, J.F., Chen, C.C., Hoffer, P.B. and Black, H.R. (1991), “Captopril Renography in the Diagnosis of Renal Artery Stenosis and the Prediction of Improvement with Revascularization: The Yale Vascular Center Experience”, Am J. Hypertens, Vol. 4, pp. 698S–705S.

9. Hansen, K.J., Tribble, R.W. and Reavis, S.W. et al. (1990), “Renal Duplex Sonography: Evaluation of Clinical Utility”, J. Vasc. Surg., Vol. 12, pp. 227–36.

10. Beregi, J.P., Elkohen, M., Deklunder, G., Artaud, D., Coullet, J.M., Wattinne, L. and Helical, C.T. (1996), “Angiography Compared with Arteriography in the Detection of Renal Artery Stenosis”, AJR Am J. Roentgenol., Vol. 167, pp. 495–501.

11. Textor, S.C. (1990), “ACE Inhibitors in Renovascular Hypertension”, Cardiovasc Drugs Ther, Vol. 4, pp. 229–35.

12. Jackson, B., Franze, L., Sumithran, E. and Johnston, C.I. (1990), “Pharmacologic Nephrectomy with Chronic Angiotensin Converting Enzyme Inhibitor Treatment in Renovascular Hypertension in the Rat”, J. Lab. Clin. Med., Vol. 115, pp. 21–7.

13. Dean, R.H., Tribble, R.W., Hansen, K.J., O’Neil, E., Craven, T.E. and Redding, J.F. (1991), “Evolution of Renal Insufficiency in Ischemic Nephropathy”, Ann Surg., Vol. 213, Vol. 446–55.

14. Guzman, R.P., Zierler, R.E., Isaacson, J.A., Bergelin, R.O. and Strandness, D.E. Jr. (1994), “Renal Atrophy and Arterial Stenosis: A Prospective Study with Duplex Ultrasound”, Hypertension, Vol. 23, pp. 346–50.

15. Bredenberg, C.D., Sampson, L.N., Ray, F.S., Cormier, R.A., Heintz, S. and Eldrup-Jorgensen, J. (1992), “Changing Patterns in Surgery for Chronic Renal Artery Occlusive Diseases”, J. Vasc. Surg., Vol. 15, pp. 1018–24.

16. Libertino, J.A., Bosco, P.J. and Ying, C.Y. et al. (1992), “Renal Revascularization to Preserve and Restore Renal Function”, J. Urol., Vol. 147, pp. 1485–7.

17. Cambria, R.P., Brewster, D.C. and L’Italien, G.J. et al. (1994), “The Durability of Different Reconstructive Techniques for Atherosclerotic Renal Artery Disease”, J. Vasc. Surg., Vol. 20, pp. 76–87.

18. Clair, D.G., Belkin, M., Whittemore, A.D., Mannick, J.A. and Donaldson, M.C. (1995), “Safety and Efficacy of Transaortic Renal Endarterectomy as an Adjunct to Aortic Surgery”, J. Vasc. Surg., Vol. 21, pp. 926–34.

19. Reilly, J.M., Rubin, B.G., Thompson, R.W., Allen, B.T., Anderson, C.B. and Sicard, G.A. (1994), “Long-term Effectiveness of Extraanatomic Renal Artery Revascularization”, Surgery, Vol. 116, pp. 784–91.

20. Tarazi, R.Y., Hertzer, N.R., Beven, E.G., O’Hara, P.J., Anton, G.E. and Krajewski, L.P. (1987), “Simultaneous Aortic Reconstruction and Renal Revascularization: Risk Factors and Late Results in Eighty-nine Patients”, J. Vasc. Surg., Vol. 5, pp. 707–14.

21. Lawrie, G.M., Morris, G.C. Jr, Glaeser, D.H. and DeBakey, M.E. (1989), “Renovascular Reconstruction: Factors Affecting Long-term Prognosis in 919 Patients Followed up to 31 Years”, Am. J. Cardiol., Vol. 63, pp. 1085–92.

22. Allen, B.T., Rubin, B.G., Anderson, C.B., Thompson, R.W. and Sicard, G.A. (1993), “Simultaneous Surgical Management of Aortic and Renovascular Disease”, Am. J. Surg., Vol. 166, pp. 726–33.

23. Weibull, H., Bergquist, P. and Bergentz, S.E. et al. (1993), “Percutaneous Transluminal Renal Angioplasty Versus Surgical Reconstruction of Atherosclerotic Renal Artery Stenosis: A Prospective Randomnized Study”, J. Vasc. Surg., Vol. 18, pp. 841–852.

24. Eisenhauer, A.C. (2000), “Atherosclerotic Renovascular Disease: Diagnosis and Treatment”, Curr Opin Nephrol Hypertens, Vol. 9, pp. 659–668.

25. Safian, R.D. and Textor, S.C. (2001), “Renal Artery Stenosis”, N. Engl. J. Med., Vol. 344, pp. 341–442.

26. Martin, L.G., Rees, C.R. and O’Bryant, T. (1994), “Percutaneous Angioplasty of the Renal Arteries”, In: Strandness, D.E. Jr, van Breda, A., eds. Vascular Diseases: Surgical & Interventional Therapy, 3rd ed. New York: Churchill Livingstone, pp. 721–41.

27. Sos, T.A., Pickering, T.G. and Saddekni, S. et al. (1984), “The Current Role of Renal Angioplasty in the Treatment of Renovascular Hypertension”, Urol. Clin. North Am., Vol. 11, pp. 503–13.

28. Blum, U., Krumme, B. and Flügel, P. et al. (1997), “Treatment of Ostial Renal-artery Stenoses with Vascular Endoprostheses After Unsuccessful Balloon Angioplasty”, N. Engl. J. Med., Vol. 336, pp. 459–65.



29. Bonelli, F.S., McKusick, M.A. and Textor, S.C. et al. (1995), “Renal Artery Angioplasty: Technical Results and Clinical Outcome in 320 Patients”, Mayo Clin. Proc., Vol. 70, pp. 1041–52.

30. Klinge, J., Mali, W.P.T.M., Puijlaert, C.B.A.J., Geyskes, G.G., Becking, W.B. and Feldberg, M.A. (1989), “Percutaneous Transluminal Renal Angioplasty: Initial and Long-term Results”, Radiology, Vol. 171, pp. 501–6.

31. Iannone, L.A., Underwood, P.L., Nath, A., Tannenbaum, M.A., Ghali, M.G. and Clevenger, L.D. (1996), “Effect of Primary Balloon Expandable Renal Artery Stents on Long-term Patency, Renal Function and Blood Pressure in Hypertensive and Renal Insufficient Patients with Renal Artery Stenosis”, Cathet Cardiovasc Diagn, Vol. 37, pp. 243–50.

32. Nordmann, A.J., Woo, K. and Parkes, R. et al. (2003), Mild aortic regurgitation (AR jet pressure half-time=420 msec.), “Balloon Angioplasty or Medical Therapy for Hypertensive Patients with Atherosclerotic Renal Artery Stenosis? A Meta-analysis of Randomized Controlled Trials”, Am J. Med., Vol. 114, pp. 44–50.

33. Krijnen, P., van Jaarsveld, B.C. and Hunink, M.G. et al. (2005), “The Effect of Treatment on Health-related Quality of Life in Patients with Hypertension and Renal Artery Stenosis”, J. Am. Coll. Cardiol., Vol. 46, pp. 776–783.

34. Leertouwer, T.C., Gussenhoven, E.J. and Bosch, J.L. et al. (2000), “Stent Placement for Renal Arterial Stenosis: Where do we Stand Ameta-analysis”, Radiology, Vol. 216, pp. 78–85.

35. van de Ven, P.J., Kaatee, R. and Beutler, J.J. et al. (1999), “Arterial Stenting and Balloon Angioplasty in Ostial Atherosclerotic Revascular Disease: A Randomized Trial”, Lancet, Vol. 353, pp. 282–286.

36. Zeller, T., Frank, U. and Muller, C. et al. (2003), “Predictors of Improved Renal Function After Percutaneous Stent-supported Angioplasty of Sever Atherosclerotic Ostial Renal Artery Stenosis”, Circulation, Vol. 108, pp. 224–2249.

37. Burket, M.W., Cooper, C.J. and Kennedy, D.J. et al. (2000), “Renal Artery Angioplasty and Stent Placement: Predictors of a Favorable Outcome”, Am Heart J., Vol. 139(1 Pt 1), pp. 64–71.

38. Zeller, T., Rastan, A. and Rothenopieler, U. et al. (2006), “Restenosis After Stenting of Atherosclerotic for the Use of Drug-eluting Stents?”, Catheter Cardiovasc Interv, Vol. 68, pp. 125–130.

39. Saproval, M., Zahringer, M. and Pattynama, P. et al. (2005), “Low-profile Stent System for Treatment of Atherosclerotic Renal Artery Stenosis; The GREAT Trial”, J. Vasc. Interv. Radiol., Vol. 16, pp. 1195–1202.

40. Henry, M., Henry, I. and Klonaris, C. et al. (2003), “Renal Angioplasty and Stenting Under Protection: The Way for the Future?”, Catheter Vardiovasc Interv., Vol. 60, pp. 299–312.

41. Holden, A. and Hill, A. (2003), “Renal Angioplasty and Stenting with Distal Protection of the Main Renal Artery in Ischemic Nephropathy: Early Experience”, J. Vasc. Surg., Vol. 38, pp. 962–968.

42. Libertino, J.A. and Beckmann, C.F. (1994), “Surgery and Percutaneous Angioplasty in the Management of Renovascular Hypertension”, Urol. Clin. North Am., Vol. 21, pp. 235–43.

43. Plouin, P.F., Chatellier, G., Darne, B. and Raynaud, A. (1998), “Blood Pressure Outcome of Angioplasty in Atherosclerotic Renal Artery Stenosis: A Randomized Trial”, Hypertension, Vol. 31, pp. 823–9.

44. Webster, J., Marshall, F. and Abdalla, M. et al. (1998), “Randomized Comparison of Percutaneous Angioplasty vs. Continued Medical Therapy for Hypertensive Patients with Atheromatous Renal Artery Stenosis”, J. Hum Hypertens, Vol. 12, pp. 329–35.

45. van Jaarsveld, B.C., Krijnen, P. and Pieterman, H. et al. (2000), “The Effect of Balloon Angioplasty on Hypertension in Atherosclerotic Renal-artery Stenosis”, N. Engl. J. Med., Vol. 342, pp. 1007–14.

46. Dorros, G., Jaff, M. and Mathiak, L. et al. (1998), “Four-year Follow-up of Palmaz- Schatz Stent Revascularization as Treatment for Atherosclerotic Renal Artery Stenosis”, Circulation, Vol. 98, pp. 642–7.



Case Report

A 64–year old man presented to emergency of a tertiary care hospital, in a drowsy state with a history of fever,

extreme weakness of both lower limbs and inability to bear weight. There were no sensations on the lower limbs; patients had to be catheterized for urinary retention. The bowels too were not clear from last two days.

Patients recently recovered from a about of high grade fever, severe body ache, joint pains and generalized weakness of about one weak duration, prior to developing this weakness.

On clinical evaluation, patient was afebrile, anasarca

was present & other general physical and system

examination was normal. Neurologically patient was drowsy but arousable. All cranial nerves examination including fundus was normal. There was hypotonia in both lower limbs, with muscle power (MRC grading) of 0/5, deep tendon reflexes were absent and planters were not elicitable. There was sensory loss of both deep and superficial dermatomes below spinal level T10. There was bowel and bladder involvement. The tone, muscle power and DTRs were normal in upper limbs.

MRI dorsal spine showed multiple T2 hyperintense areas are noted in dorsal cord without any significant expansion suggestive of transverse myelitis.

Clinically possibility of ACUTE TRANSVERSE MYELITIS (Post viral) was kept and patient was investigated accordingly.

Routine investigation done showed normal complete blood counts, mild Transaminitis with deranged renal function (urea 49.40, creatinine -1.5, Na+129).

Malarial antigen test, typhi dot IgM, Widal test, Dengue NS1 antigen, Dengue serology, ELISA for HIV I and II, HBsAg and anti-HCV were normal. Procalcitonin, PT/INR, APTT were normal. D-Dimer was raised (3028 ng/ml). Connective tissue and vasculitic profile screening (ANA, dsDNA, C anca, P anca) was normal. Blood Culture and urine culture were normal.

Chest X-Ray, USG whole abdomen, Echocardiography, Peripheral Vascular Doppler (arterial and venous) both lower limbs were normal. NCV both lower limbs were also normal. NCCT Head was normal. NCCT chest showed plate atelectasis in basal segment of bilateral lobes.

MRI Dorsal spine done showed on T2 weighted images-Hyperintense signal at multiple segments in dorsal spine without any expansion s/o Myelitis. MRI Brain was normal and MRI LS spine showed degenerative changes. CSF examination was done which showed two cells mainly mononuclear, glucose and ADA levels were normal, proteins were raised (102 mg/dl).

The Chikungunya serology by real time loop-mediated isothermal Amplification (RT-LAM)-Polymerase chain reaction was positive.

Patient was prescribed acyclovir and methyl prednisolone pulse for five days. Physiotherapy of the limbs was done. Patients however did not show much improvement. After one week a re peat MRI thoracic spine with contrast was done which too did not show any

1Consultant PhysicianMetro Hospitals & Heart Institute, Noida–201301, UP2Sr. Consultant PhysicianMetro Hospitals & Heart Institute, Noida–201301, UP3Consultant NeurologistMetro Hospitals & Heart Institute, Noida–201301, UP4RadiologistMetro Hospitals & Heart Institute, Noida–201301, UP5,6Associate ConsultantMetro Hospitals & Heart Institute, Noida–201301, UP

Myelitis: A Rare Complication of Chikungunya FeverKiran Seth1, S. Chakravorty2, Kapil Singhal3, Sayeed Amir4, Prashant Arun5 and Piyush Sood6

ABSTRACTIn a recent outbreak of chikungunya fever in many part of the country, we observed Myelitis, a rare neurological presentation of chikungunya fever. Chikungunya is a mosquito-borne virus. It was first identified more than 60 yrs. ago in modern day Tanzania, causing outbreaks of acute febrile polyarthralgias. Here we report a case of Chikungunya who presented with features of transverse Myelitis.

Case Reports



significant improvement. In further follow up in OPD patient showed partial neurological improvement.

DiscussionChikungunya fever is an arboviral illness caused

by an RNA virus belonging to genus alpha virus and family togaviridae. The virus is spread between people by two types of mosquitos: Aedes albopictus and Aedes aegypti. In India the first outbreak was reported in 1963[1] in Calcutta. The second epidemic was seen in December 2005. Recently in 2016 was saw outbreak of the disease in many part of the country.

It is a benign self-limiting febrile illness associated with itchy rash polyarthralgias. Oral ulcers and neurological complication is very rare and infrequent. Economopoulos et al.[2], reported neurological manifestations in 24.1% patients with Chikungunya infection whereas Chandak et al., observed it in 16.3% of patients and Rampal et al.[3,4], in as much as 33% patients .

The most common form of neurological involvement observed was Encephalitis. Myelitis was seen in only 7 out of the 300 patients with Chikungunya virus infection by Chandak et al., and in only 3 of the 60 patients with Chikungunya virus infection studied by Rampal et al., The other neurological presentation include Guillain-Barre syndrome (GBS), cerebellar syndrome, myelitis, external opthalmoplegia, facial palsy, sensorieneural deafness and

optic neuritis. The chief target cell of Chikungunya virus is the fibroblast which has been seen in various animal experimental studies. There is tropism for muscle, joint, skin & connective tissues, causing various symptoms. The macrophages are activated leading to arthritis and myositis.

The Pathophysiology of neurological involvement in Chikungunya infection has not been established but reports of association with neurological involvement in animal experimental studies strongly point towards neurotropism of the virus[5].

ConclusionThe Chikungunya infection though is considered a

benign illness with the risk of death 1 in 1000[6] should be considered as a possible etiology while evaluating patients with Transverse Myelitis. All patients with a history of fever with joint pain and history of Chikungunya infection should be followed up for neurological complications.

Reference 1. Morrison, T.E. (2014), “Re-emergence of chikungunya

virus”, J Virol, Vol. 88, pp. 11644–47. http://dx.doi.org/10.1128/JVI. 01432-14. Epub 2014 July 30. PMID: 25078691.

2. Powers, A.M. and Logue, C.H. (2007), “Changing Patterns of Chikungunya Virus: Re-Emergence of a Zoonotic Arbovirus”, J Gen Virol, Vol. 88, pp. 2363–77.

3. Powers, A.M., Brault, A.C., Tesh, R.B. and Weaver, S.C. (2000), “Re-emergence of Chikungunya and O’nyong-Nyong Viruses: Evidence for Distinct Geographical Lineages and Distant Evolutionary Relationships”, J Gen Viral, Vol. 81, pp. 471–9.

4. Chandak, N.H., Kashyap, R.S., Kabra, D., Karandikar, P., Saha, S.S. and Morey, S.H. et al. (2009), “Neurological Complications of Chikungunya Virus Infection”, Neurol India, Vol. 57, pp. 177–80. [PubMed]

5. Rampal , Sharda M. and Meena, H. (2007), “Neurological Complications in Chikungunya Fever”, J Assoc Physicians India, Vol. 55, 765–69.[PubMed]

6. Rajapakse, S., Rodrigo, C. and Rajapakse, A. (2010), “Atypical Manifestations of Chikungunya Infection”, Transactions of the Royal Society of Tropical Medicine and Hygiene, Vol. 104, pp. 89–96. [PubMed]

7. Wadia, R.S. (2007), “A Neurotropic virus (Chikungunya) and a Neuropathic Aminoacid (Homocysteine)”, Ann Indian Acad Neurol, Vol. 10, pp. 198–213.

8. National Institute of Communicable Disease, New Delhi. Chikungunya Fever. CD Alert. 2006, Vol. 10, pp. 6–8.



“Always laugh when you can, it is cheap medicine”

George Gordon Byron

“Let food be thy medicine and medicine be thy food”

Hippocrates

“Wherever the art of Medicine is loved, there is also a love of

Humanity”

Hippocrates

MEDICAL QUOTATIONS

“The art of medicine consists of amusing the patient while

nature cures the disease”

Voltaire



“Declare the past, diagnose the present, foretell the future”

Hippocrates

“As to diseases, make a habit of two things—to help, or at

least, to do no harm”

Hippocrates



Yoshinori Ohsumi won the 2016 Nobel Prize

Nobel Prize-2016 for Cell Recycling (Autophagy) Molecular biologist Prof . Yoshinori Ohsumi has won the 2016 Nobel Prize in Physiology Medicine for his work on AUTOPHAGY: The processes by which the cell digests and recycles its own components. The 71-year-old Ohsumi, professor at the Tokyo Institute of Technology in Yokohama, has been recognized for experiments since 1990s that used baker’s yeast (Saccharomyces cerevisiae) to identify genes that control how cells destroy their own contents. Similar mechanisms operate in human cells and are sometimes involved in genetic disease. The term autophagy is from the Greek for ‘self-eating’—was coined in 1963 by the Belgian biochemist Christian de Duve, who saw how cells broke down their parts inside a waste-processing sac the lysosome. Biologists now understand that this process is fundamentally important to living cells.

Ohsumi first started studying autophagy in 1988, “it was kind of a sleepy backwater of a research topic. “It was basically considered the garbage-disposal system of the cell—just bulk, non-specific degradation of junk”

Interest in the field skyrocketed when, in 1999, Beth Levine (now at the University of Texas Southwestern Medical Center in Dallas) and her colleagues reported that a mammalian autophagy gene could suppress tumour growth. The finding launched widespread efforts to learn more about autophagy’s role in cancer. Disruptions in Autophagy have also been linked to Parkinson’s disease, type 2 diabetes and other disorders—and research is ongoing to develop drugs that can affect the process. The complex role of Autophagy 0in cancer has become more detailed: the process seems to inhibit tumours in the early stages of growth, but can also fuel cancer once it has spread.

WHAT IS AUTOPHAGY? The word derives from the Greek auto (self) and phage in (to eat). So the word literally means to eat oneself. Essentially, this is the body’s mechanism of getting rid of all the broken down, old cell machinery

(organelles, proteins and cell membranes) when there’s not enough energy to sustain it. It is a regulated, orderly process to degrade and recycle cellular components. Autophagy is different from apoptosis (Total replacement of cell)

Apoptosis meaning as programmed cell death. Cells, after a certain number of division, are programmed to die, this process is essential in maintaining good health.

When cells become old and junky. It is better that they be programmed to die when their useful life is done. It sounds really cruel, but that’s life. That’s the process of apoptosis, where cells are pre-destined to die after a certain amount of time.

Autophagy–Replacing Old Parts of the CellInstead of killing off the entire cell (apoptosis), body wants to replace some cell parts. That is the process of autophagy, where sub-cellular organelles are destroyed and new ones are rebuilt to replace it.

Old cell membranes, organelles and other cellular debris can be removed. This is done by sending it to the lysosome which is a specialized organelle containing enzymes to degrade proteins of cellular defines.

One of the key regulators of autophagy is the kinase called mammalian target of rapamycin (mTOR). When mTOR is activated, it suppresses autophagy, and when dormant, it promotes it.

What activates autophagy?Nutrient deprivation is the key activator of autophagy.

Remember that glucagon is kind of the opposite hormone to insulin. It’s like the game we played as kids–‘opposite day’. If insulin goes up, glucagon goes down. If insulin goes down, glucagon goes up. As we eat, insulin goes up and glucagon goes down. When we don’t eat (fast) insulin goes down and glucagon goes up. This increase in glucagon stimulates the process of autophagy. In fact, fasting (raises glucagon) provides the greatest known boost to autophagy.

This is in essence a form of cellular cleansing. The body identifies old and substandard cellular equipment and marks it for destruction. It is the accumulation of all this junk that may be responsible for many of the effects of aging.

Fasting is actually far more beneficial than just stimulating autophagy. It does two good things. By stimulating autophagy, we are clearing out all our old, junky proteins and cellular parts. At the same time, fasting also stimulates growth hormone, which tells our body to start producing some new snazzy parts for the body so really giving our bodies the complete renovation.

Autophagy is a highly regulated process. If it runs amok, out of control, this would be detrimental, so it must be carefully controlled. In mammalian cells, total depletion of amino acids is a strong signal for autophagy, but the role of individual amino acids is more variable. However, the plasma amino acid levels vary only a little. Amino acid

Medical History



signals and growth factor/ insulin signals are thought to converge on the mTOR pathway–sometimes called the master regulator of nutrient signalling.

So, during autophagy, old junky cell components are broken down into the component amino acids (the building block of proteins). What happens to these amino acids? In the early stages of starvation, amino acid levels start to increase. It is thought that these amino acids derived from autophagy are delivered to the liver for gluconeogenesis. They can also be broken down into glucose through the tricarboxylic acid (TCA) cycle. The third potential fate of amino acids is to be incorporated into new proteins.

The consequences of accumulating old junky proteins all over the place can be seen in two main conditions– Alzheimer’s disease (AD) and cancer. Alzheimer ’s disease involves the accumulation of abnormal protein–either amyloid beta or Tau protein which gums up the brain system. It would make sense that a process like autophagy that has the ability to clear out old protein could prevent the development of AD.

What turns off autophagy? Eating. Glucose, insulin (or decreased glucagon) and proteins all turn off this self-cleaning process. And it doesn’t take much. Even a small amount of amino acid (leucine) could stop autophagy cold. So this process of autophagy is unique to fasting–something not found in simple caloric restriction or dieting.

There is a balance here, of course. You get sick from too much autophagy as well as too little. Which gets us back to the natural cycle of life–feast and fast. Not constant dieting. This allows for cell growth during eating and cellular cleansing during fasting–balance. Life is all about balance.

Prof. Om Kumari GuptaConsultant PhysicianMetro Hospital Noida

ASSOCIATION OF PHYSICIANS OF INDIA

NOIDA CHAPTER

T-21, SEC-11, NOIDA, (U.P.)-201301 Website: www.apinoidachapter.com



The Editorial Process

The manuscripts will be reviewed for possible publication with the understanding that they are being submitted

to one journal at a time and have not been published, simultaneously submitted or already accepted for publication elsewhere. The Editors review all submitted manuscripts initially. Manuscripts with insufficient originality, serious scientific flaws or absence of importance of message are rejected. The journal will not return the unaccepted manuscripts. Other manuscripts are sent to two or more expert reviewers without revealing the identity of the contributors to the reviewers. Within a period of 8 to 10 weeks, the contributors will be informed about the reviewers’ comments and acceptance/rejection of manuscript.

Articles accepted would be copy edited for grammar, punctuation, print style and format.

Types of Manuscripts and word limits:Original Articles: Randomized controlled trials,

intervention studies, studies of screening and diagnostic test, outcome studies, cost effectiveness analyses, case-control series, and surveys with high response rate. Up to 2500 words excluding reference and abstract.

Review Articles: Systemic critical assessments of literature and data sources. Up to 3000 words excluding reference and abstract.

Case Reports: New/interesting/very rare cases can be reported. Cases with clinical significance or implications will be given priority, whereas, mere reporting of a rare case may not be considered. Up to 1000 words excluding reference and abstract and up to 10 references.

Short Reports: These are usually short technical reports about a procedure or technique that is unique or new or in the experience of the author of interest to the readers.

Letter to the Editor: New/interesting/very rare cases with clinical significance. Up to 600 words excluding reference and abstract and up to 5 references.

Letter to the Editor: Should be short, decisive observation. They should not be preliminary observations that need a later paper for validation. Up to 400 words and 4 references.

Neuro Image: Classical clinical/radiological/pathological image up to 250 words and 4 references.

Announcements of conferences, meetings, courses, awards, and other items likely to be of interest to the readers should be submitted with the name and address of the person from whom additional information can be obtained. Up to 100 words.

Limits for number of images and tables: for all the above-mentioned categories the number of image and table should not be more than one per 500 words.

Manuscript Preparation GuidelinesArticles submitted to Journal of Internal Medicine of India-UP should conform to the guidelines indicated below. Before you submit, please study the author checklist provided at

the end of this document. Following is the chronological order of topics to be included in the article:Title, Abstract, Keywords, Introduction, Concept headings (include statistical methodology, if any), Discussion, Conclusion, Acknowledgements (If any), References

Cover LetterThe covering letter should be written by the corresponding author indicating how the manuscript is suitable for publication in Journal of Internal Medicine of India. All authors names are to be included in the letter (preferably along with their signatures) stating the article has not been published elsewhere or communicated to any other publication apart Journal of Internal Medicine of India. If the article is authored by a student, it is requested that he/she obtain the approval of the institution department prior to submitting the article.

Electronic FormatsAuthors are requested to send their articles in MS Word (.doc) format. In case of any difficulty with the manuscript submission process or concern regarding the suitability of your files, please contact us at [email protected]

Article TitleThe title should be concise and specific to the topic of the article Avoid using abbreviations in the title. Titles should be presented in title case, meaning that all words except for prepositions, articles, and conjunctions should be capitalized. All botanical names should be in italics.

E.g. An Experimental Study of Classification Algorithms for Crime Prediction

Author names & AffiliationsProvide first names or initials (if used), middle names or initials (if used), and surnames for all authors. Affiliation details should include—department, university or organization, city, state and country for all authors. One of the authors should be designated as the corresponding author with asterisk (*) against his/ her name. Only the corresponding author’s email address should be provided in the article. It is the corresponding author’s responsibility to ensure that the author list and the summary of the author contributions to the study are accurate and complete.

Abstract & KeywordsThe abstract introduces the article and should not exceed 300 words. It should mention the techniques used without going into methodological detail and should summarize the most important results. Please do not include any citations in the abstract and avoid using abbreviations if possible.

Authors should provide 4–6 keywords for indexing purposes. Keywords should be written in title case and separated by comma. Avoid general and plural terms and multiple concepts (avoid, for example, ‘and’, ‘of’).

Manuscript



HeadingsFor a better understanding of the content in the article, we encourage authors to number the article headings in Arabic style format. Headings should follow title case, meaning that all words except for prepositions, articles, and conjunctions should be capitalized. All botanical names should be in italics.

For Example: 1. Finite Element Modelling (FEM)1.1 Model Description

AbbreviationsAll abbreviations should be defined on first use in the text along with the abbreviation in parenthesis. E.g. Magnetic Resonance Imaging (MRI)

Units and SymbolsSymbols should be used while referring to alpha, beta, mu, etc (Ex: α, β, µ, etc). All units to follow the International System of Units (SI units).

Figures: General guidelinesFigures Format & Resolution: Authors are requested

to supply high-resolution versions of the figures in TIFF, JPEG or EPS format. We require that figures be created at a minimum resolution of 300 ppi.

File Size: The file sizes should not exceed 20 MB.File Naming: Naming of figure files should be simple

indicating the serial number and last name of author. E.g. if author’s name is Bob Marley, Figure 1 should be named as “Fig. 1_Marley”.

Figure Submission: Figures should be submitted after uploading the article (in step 4 of the submission process in supplementary files). In case of multiple files, upload the figures in order. E.g. Fig. 1 should be uploaded first followed by Fig. 2, 3 and so on.

Citation: All figures must be cited in the text and authors should indicate where they are to be inserted in the text. E.g. <insert figure 1 here>.

Figure Captions: These have to be included in the text and provided sequentially at the end of the article. The captions should be short having 10–15 words in sentence case style. E.g. Fig. 1. Percentage of detection rate vs. number of nodes.

Permissions: Authors should obtain permission from authors for copyright figures and tables before submitting to Journal of Internal Medicine of India.

All figures will be published under a Creative Commons Attribution License, which allows them to be freely used, distributed, and built upon as long as proper attribution is given. Please do not submit any figures that have been previously copyrighted unless you have express written permission from the copyright holder to publish under the CCAL license.

Tables: General guidelinesTables should be included in the text file at the end of

the article.

All Tables should have a concise title and written as Table 1 with a period (.).

E.g. Table 1. Stimulation settingsFootnotes can be used to explain abbreviations. Tables

extending beyond 1 page should be avoided.AcknowledgmentsPeople who contributed to the work but do not fit the

criteria for authors should be listed in the Acknowledgments, along with their contributions. Authors are requested to ensure that anyone named in the Acknowledgments agrees to being so named.

ReferencesOnly published or accepted manuscripts should be included in the reference list. Meetings, abstracts, conference talks, or papers that have been submitted but not yet accepted should not be cited.

In Text Citations: References cited in text should conform to the Vancouver style. Please refer the Vancouver Style of Referencing.

Reference List: This should only contain references to those works which you have cited in your text. It should appear at the end of your text. It should be arranged numerically by citation number. Examples are indicated below.

Overview of the Production ProcessUpon acceptance of the paper, authors will be contacted by the production team of Journal of Internal Medicine of India. The manuscript will be processed through editing and scrutinized for any missing elements or disparities. Authors will be contacted by the production team and asked to supply the missing information in their paper. This will be the final stage for authors to send amendments to the manuscript. Upon finalization of the edited files, the files will be processed through typesetting to generate first proofs. Authors will receive the first proofs of their article to resolve any pending queries. Authors are advised not to send any corrections at the proofs stage and are requested to co-operate with the production team to ensure smooth workflow and timely publication of the journal issue.

Author Checklist before SubmissionAre you ready to submit your article? We recommend you check these items one final time before uploading the article on our website. In case of any difficulty in submitting your article, please get in touch with us at [email protected]

• Cover letter with all author names• Manuscript is adhering to guidelines• All Author Affiliations provided• Corresponding Author’s email address provided• All Figures and tables are called out in the manuscript• All Figures have been uploaded on the online

submission platform



RDW as a Predictor of All Cause Mortality Among Non Anaemic Patients

RDW is a parameter that measures the variation in RBC size and volume. It is represented statistically as

coefficient of variation (RDW CV) or standard deviation (RDW SD). RDW SD is the actual measurement of width of the RBC size. It is not influenced by MCV. RDW-CV is calculated as sd of RBC volume/MCV X 100%. Efforts are being made to establish RDW as a predictor of mortality in both middle aged and older patients. Studies being done in this direction show that an increased RDW may be a strong predictor of mortality in middle aged or older patients1. Numerous causes of increased RDW were taken into account such as cancer, CVD, Iron deficiency anaemia, folate and Vit-B12 deficiency, mixed deficiency, recent hemorrhage. Pooled data from many internationally recognized studies indicate that increased RDW width may be associated with increased mortality in CVD patients. Associations were made which were independent of possibly confounding variables. Even when participants with raised RDW due to nutritional deficiencies were excluded it still remained a strong predictor of mortality2,3,4. More importantly that It predicted mortality in non anaemic patients. Even though the exact mechanism that correlate the RDW with survival are unknown, systemic factors that change the erythrocyte homeostasis such as inflammation and oxidative stress play a probable role. Inflammation might be able to increase the RDW by inhibiting iron metabolism but also by decreasing the production and response of Red blood cells to erythropoietin or by decreasing the red blood cell viability. It was observed by Ferruci and colleagues that higher levels of inflammation were associated with higher erythropoietin concentration among non anaemic patients. A number of studies have shown that pro-inflammatory cytokines suppress erythropoietin gene expression, down regulates erythropoietin receptor expression, and reduce erythrocyte life span. In addition to inflammation oxidative stress might also contribute to anisocytosis. While erythrocytes have tremendous antioxidant capacity and serve as primary oxidative sink they are prone to oxidative damage that reduces red cell survival. In a recently conducted randomized control trial of heart failure patients, Felker and colleagues showed that patients With RDW>15.8% had nearly 2 fold increased

risk of CVD death or hospitalization as well as death from any cause compared to those with RDW<13.3%. This finding was validated, by Felker et al. also showed a 2 fold increased mortality risk comparing the highest RDW quintile (>15.5%) to lowest (13%) in a separate clinical cohort of Heart failure patients2-5. Similarly Tonnelli et al analyzed data from a randomized control trial with patients with CAD and reported that death was twice as likely in patients with RDW >13.8 % versus those with RDW <12.7%. Finally Anderson reported that risk of death was 3 times higher in patients undergoing cardiac catheterization with RDW>14% relative to those with RDW < 12.7%. However all these studies were not able to provide any data on nutritional status or inflammation. Studies are now being done on adults aged 45 or older with subjects adjusted for nutritional status in the post supplementation era.

To conclude RDW is a relatively easy and inexpensive test and is widely available to the general population. It can become an effective screening tool for mortality in patients aged 45 or older. Further studies are still required to establish the clinical utility of this test for the same.

References1. Patel, K.V., Ferrucci, L., Ershler, W.B., Longo, D.L. and

Guralnik, J.M. (2009), “Red Blood Cell Distribution Width and the Risk of Death in Middle-aged and Older Adults”, Arch Intern Med., Vol. 169, pp. 515–23.

2. Allen, L.A., Felker, G.M., Mehra, M.R., Chiong, J.R., Dunlap, S.H. and Ghali, J.K. et al. (2010), “Validation and Potential Mechanisms of Red Cell Distribution Width as a Prognostic Marker in Heart Failure”, J Card Fail., Vol. 16, pp. 230–8.

3. Pascual-Figal, D.A., Bonaque, J.C., Redondo, B., Caro, C., Manzano-Fernandez, S. and Sa´nchez-Mas, J. (2009), et al., “Red Blood Cell Distribution Width Predicts Long-Term Outcome Regardless of Anaemia Status in Acute Heart Failure Patients”, Eur J Heart Fail., Vol. 11, pp. 840–6.

4. Jackson, C.E., Dalzell, J.R., Bezlyak, V., Tsorlalis, I.K., Myles, R.C. and Spooner, R., et al. (2009), “Red Cell Distribution Width has Incremental Prognostic Value to B-type Natriuretic Peptide in Acute Heart Failure”, Eur J Heart Fail., Vol. 11, pp. 1152–4.

5. Van Kimmenade, R.R., Mohammed, A.A., Uthamalingam, S., Meer, Van Der P., Felker, G.M. and Januzzi, Jr J.L. (2010), “Red Blood Cell Distribution Width and 1-year Mortality in Acute Heart Failure”, Eur J Heart Fail., Vol. 12, pp. 129–36.

Knowledge Forum











Date Members Non Members Students Members

Spouse Corporate

Up to 31 Oct 2016 1200 1500 750 1000 2000Up to 31 Dec 2016 1500 2000 750 1200 2500Up to 28 Feb 2017 2000 2500 1000 1500 30001st Mar to Spot 2500 3000 1200 2000 5000

REGISTRATION CHARGES

Organizing Committee RSSDI-UPCON 2017PatronDr. Brij Mohan

Organizing SecretaryDr. Deepak Yagnik

Scientific ChairmanDr. Anuj Maheswari

Organizing ChairmanDr. Rishi Shukla

TreasurerDr. S.C. Wadhwani

Scientic SecretaryDr. (Capt) Bhaskar Ganguli

State Co-ordinatorDr. N.S. Verma

Governing Body (U.P.) ChapterExecutive PatronsProf. J.K. AgarwalProf. A.R. SircarProf. D.K. HazaraProf. Sarita Bajaj

Governing Council MembersDr. N.K. SoniDr. Atul Kulshrestha Dr. Anand SinghDr. Rishi ShuklaDr. Aloke Kumar Gupta

Co-opted MembersDr. S.K. SinghDr. G.P. RaiDr. R.R. SinghDr. Deepak YagnikDr. Sanjiv MittalDr. Subodh Chandra

ChairmanProf. Kamlakar Tripathi

Vice ChairmanDr. Brij Mohan

Chapter Joint SecretaryDr. Kauser Usman

Chapter SecretaryDr. Anuj Maheshwari

Chapter TreasurerDr. Narsingh Verma



API-UP CHAPTERMEMBERSHIP FORM

To,Honorary SecretaryAssociation of Physician of India ( U.P. Chapter),Dept. of Medicine, K.G’s. Medical University, Lucknow–226003.

We hereby propose the admission ofName (in full & block letters) :

Father’s Name ______________________________________________________________Gender M FQualification : _____________________________________________________________________________________________( Mention the discipline in which postgraduate qualification obtained)Institution/University : _____________________________________________________________________________________Year of Obtaining first postgraduate qualification : _____________________________________________________________API Member (Yes / No), If yes Membership No. _______________________________________________________________Mailing Address : __________________________________________________________________________________________ __________________________________________________________________________________________________________Contact No. : __________________________E – mail: ____________________________________________________________Permanent Address : _________________________________________________________________________________________________________________________________________________________________________________________________Applied for: (Please appropriate after reading the conditions overleaf)Life Member(LM) Associate Member(AM) Provisional Associate Member (PAM) (For PG Students)To the best of our knowledge and belief, the above particulars are correct and we consider him/her a fit and proper person to be admitted as a member of the association._______________________ ___________________________Signature of Proposer Signature of Seconder

Name ________________________________ Name________________________________________API Membership No.___________________ API Membership No. __________________________UP API Membership No. _______________ UP API Membership No._______________________

Life membership Subscription (Inclusive of Admission Fee) Rs. 4000/- ( Rupees Four thousand only) is herewith enclosed vide Bank Draft No. __________________ Dated ____________ in Favour of “API-U.P. CHAPTER” Payable at Lucknow.

Subject to approval of the Governing Body in a Special Meeting, I agree to become a member and if admitted, to abide by the Rules and Regulations of the Association._______________________Signature of Candidate....................................................................................................................................................................................................................

For Office UseAdmitted / Not Admitted Vide Governing Body Meeting Dated : ________________ held at __________________Payment received Rs. ____________________ Vide Bank Draft No. ________________ dated ___________________drawn on ___________________________________Bank.Membership No.: L/AM/PAM _______________



Documents to be Enclosed:

• Photocopy of registration with UP Medical Council of India or the Central Medical Council of India.• Photocopy of the postgraduate qualification.

There are Two Categories of Membership:1. Life Member: Any person who is a member of Central body of Association of Physicians of India and is residing in Uttar Pradesh of India is eligible to become life member of U.P. Chapter. Central API membership is permissible to those who hold a postgraduate degree M.D. or D.M. or its equivalent in Internal Medicine from any institution or University recognised by the Medical Council of India or approved by the Governing body of the Association of Physicians of India provided he/she is not engaged in general or dispensing practice. Internal Medicine includes specialities such as Cardiology, Gastroenterology, Diabetology, Nephrology, Neurology, Clinical Hematology, Chest, Immunology, Rheumatology, Medical Oncology, Psychiatry, Pediatric Medicine, Dermatology, Radiation Medicine, Ultrasonography and others approved by Governing Body.

2. Associate Life Member: There are three categories of Associate Life Member:I. Those who are eligible to become Ordinary or Life member of Central body of API but have not become so far.II. Any person holding a postgraduate degree or diploma recognized by Medical Council of India in any branch of

Medical Science but is not eligible to become life member is eligible to become Associate Life Member.III. Provisional Associate Member: A Postgraduate student in Medicine may be enrolled as “Provisional Associate

Member” on payment of full membership fees of the chapter. Such Membership will ordinarily last for five years unless the member informs about completion of postgraduate courses. In such cases he/she will be considered for Life Member/ Associate Life Members as per fulfillment of the requirement.

Note:• Associate Life Member shall not have right to vote, propose, second or contest any position of the governing body. They shall also

not be entitled for participation, except when stated otherwise, in any “Award Session” or for recommendation for any distinction conferred by the U.P. Chapter.

• Photocopy of this form can also be used.





www.groupexcelindia.com

91 A, Ground Floor, Pratik Market, Munirka, New Delhi-110067Call: +91-11-2671 1755/ 2755/ 3755/ 5755• Fax: 011-2671 6755e-mail: [email protected] • Web: www.groupexcelindia.com

Publishing Consultancy

Designed and P

rinted by: Excel P

rinting Universe, e-m

ail: [email protected]

, Website: w

ww

.groupexcelindia.com

RNI No.: 69152/98

Journal ofINTERNAL MEDICINE OF INDIA

Vol. 11 No. 2 January 2017 ISSN: 0972–1096

OFFICIAL PUBLICATION OF ASSOCIATION OF PHYSICIANS OF INDIA – U.P. CHAPTER

U.P. CHAPTER


JIMIEditor-in-Chief Dr. S. Chakravorty