Rajiv Gandhi University of Health Sciences Karnataka



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|RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES |

|BANGALORE, KARNATAKA |

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|ANNEXURE II |

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|PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION |

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|1 |NAME OF THE CANDIDATE & ADDRESS |Dr. AKKAMAHADEVI V NIPANAL |

| | |POST GRADUATE IN MD MEDICINE, |

| | |BANGALORE MEDICAL COLLEGE & RESEARCH |

| | |INSTITUTE, KR ROAD, FORT, BANGALORE-560002 |

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|2 |NAME OF THE INSTITUTION |BANGALORE MEDICAL COLLEGE & RESEARCH INSTITUTE, KR ROAD, FORT, BANGALORE-560002 |

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|3 |COURSE OF STUDY AND SUBJECT |MD IN MEDICINE |

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|4 |DATE OF ADMISSION TO THE COURSE |29-07-2013 |

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|5 |TITLE OF TOPIC |“A STUDY OF ESTIMATION OF CEREBROSPINAL FLUID C-REACTIVE PROTEIN AND ADENOSINE DEAMINASE |

| | |LEVEL IN DIFFERENTIAL DIAGNOSIS OF MENIGITIS IN ADULTS.” |

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|6. |BRIEF RESUME OF INTENDED WORK: |

| |Need for study: |

| |Acute infections of the nervous system are among the most important problems in medicine because early recognition, efficient decision-making, and |

| |rapid institution of therapy can be lifesaving. These distinct clinical syndromes include acute bacterial meningitis, viral meningitis, |

| |encephalitis, focal infections such as brain abscess and subdural empyema, and infectious thrombophlebitis.[1] |

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| |In healthy the median concentration of serum C-Reactive protein is 0.8mg/l. C-Reactive protein concentrations in the CSF are seven fold lower than |

| |those of serum. Meningial irritation stimulates C-Reactive protein production. Its production is controlled by Interleukin-6 and it binds to |

| |polysaccharides present in many bacteria, fungi and protozoal parasites.[2] |

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| |The activity of AD is subject to changes depending upon the degree of activity of the cell i.e. whether differentiation or proliferation occurs. |

| |ADA has 2 principle isoenzymes ADA1, ADA2 which have different optimal pH, Michaeli’s constant and relative substrate specificity patterns. ADA2 is|

| |the major component (73%) of the activity of total ADA in the serum of healthy persons. ADA2 has much greater affinity for adenosine and found only|

| |in macrophages and monocytes, which release it when stimulated in the presence of live organisms.[3] which in turn increases the CSF levels. |

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| |Clinical differentiation of pyogenic meningitis from TBM and viral meningitis becomes difficult in acute conditions. Reliable, cost effective, |

| |rapid diagnostic tests which can be performed in any standard pathology laboratory could be of help in the differentiation of various types of |

| |meningitis in adults. In this regard, C - Reactive protein level and Adenosine deaminase activity can be used as rapid tests in the differential |

| |diagnosis of meningitis. |

| |C – Reactive protein – Increased in Pyogenic meningitis.[4-6] |

| |ADA –Increased Tubercular meningitis[7] |

| |Viral meningitis- Low levels of ADA and C-Reactive protein. |

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| |Review of Literature: |

| |Tillet and Francis, French investigators in 1930 described a substance that was present in the sera of acutely ill patients which was able to bind |

| |to the cell wall c-polysaccharide of streptococcus pneumoniae and agglutinate the organisms. In 1941, the substance was shown to be a protein and |

| |given the name C-reactive protein (CRP).[3] |

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| |Kashyap et al[7] did one of the largest studies on 117 patients of TBM and showed that the mean CSF ADA activity was found to be significantly |

| |higher in CSF of TBM patients, 14.31 ± 3.87, |

| |than in the CSF from non-TBM infectious meningitis, 9.25 ± 2.14. |

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| |CSF ADA activity is raised in TBM and their use has been suggested to help differentiate TBM from viral and bacterial meningitis.[7-10] |

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| |C reactive protein can help differentiate pyogenic from non-pyogenic meningitis. Large number of studies conducted around the world suggests that |

| |CRP levels in the CSF are higher in pyogenic meningitis compared to non-pyogenic meningitis and hence aid in the differential diagnosis and |

| |management of meningitis.[4-6] |

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| |In a study conducted by Vaishnavi C et al[11] CRP in CSF was significantly higher in patients with pyogenic meningitis compared to TBM. Authors |

| |concluded that the estimation of CRP in the differential diagnosis of meningitis might be made to give a preliminary diagnosis of meningitis. |

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| |The study by Hemavani V et al[5] concluded that CSF CRP determination can be of value to differentiate pyogenic versus other microbial meningitis |

| |etiology. However, it cannot differentiate between tuberculosis, fungal and viral meningitis. |

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| |A recent meta-analysis by Gerdes LU et al[12] suggested that a negative CRP test in either CSF or serum can be used with a very high probability to|

| |rule out bacterial meningitis. |

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| |6.3 Objectives of the study: |

| |To estimate the C reactive protein and Adenosine deaminase levels in CSF of patients with meningitis. |

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| |To evaluate whether C-reactive protein and Adenosine deaminase levels could be used to differentiate the various types of meningitis in adults. |

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| |MATERIALS AND METHODS: |

| |7.1 Source of data: |

| |Patients admitted and willing to give consent in the medicine department at Victoria and Bowring hospitals, BMCRI, Bangalore. |

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| |Methods of collection of data: |

| |Study design: Cross sectional study |

| |Study period: October 2013 to May 2015 |

| |Place of study: Inpatient department of Medicine, at Victoria and Bowring Hospital attached to BMCRI, Bangalore. |

| |Sample size: Minimum of 50 patients. |

| |Inclusion Criteria : |

| |Age > 18 years. |

| |Clinical features suggestive of meningitis |

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| |Exclusion Criteria: |

| |Age < 18 years. |

| |A patient with acute infections at sites other than central nervous system. |

| |Patients in whom lumbar puncture is contraindicated. |

| |Associated severe hepatic dysfunction. |

| |Females on oral contraceptives and intrauterine device. |

| |Severe dyslipidemia. |

| |Patients on steroid. |

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| |Methodology: |

| |Written informed consent will be taken from the patients.[ANNEXURE I] |

| |Data will be collected by pretested semi structured questionnaire, clinical examination and investigations.[ANNEXURE III] |

| |An estimation of CSF ADA and C-Reactive protein level will be done for all the patients satisfying the inclusion and exclusion criteria. |

| |Statistical analysis: |

| |All quantitative data like age, vital signs and investigations will be presented as mean and standard deviation with 95% confidence intervals. |

| |All qualitative data like sex, symptoms, baseline medical characteristics, clinical examination findings will be presented as frequency and |

| |percentages. |

| |Student's ‘t’ and chi-square (λ2) test Will be used to analyze the CSF ADA and CRP level for statistical significance |

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| |Does the study require any investigation to be conducted on patients or animals specify? Yes. The following investigations are required. |

| |1) CSF CRP level |

| |2) CSF ADA level |

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| |Has the ethical clearance been obtained from ethics committee of your Institution in case |

| |of 7.3? |

| |“YES”. The ethical clearance has been obtained from the ethical committee of Bangalore Medical College and Research Institute, Bangalore. |

| |LIST OF REFERENCES: |

| |1. Karen L.Roos,Kenneth L.Tyler. In Longo,Fauci,Kasper et all. Harrison’s principles of internal medicine. 18th edition: United states of America: |

| |Mc Graw Hill: 2012; 381:3410-20. |

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| |2. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest |

| |2003; 111:1805-12. |

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| |3.Rifai N, Warnick RG. Teitz Textbook Of Clinical Chemistry & Molecular Diagnostics. 4thed: Butterworth Heinemann; 1999: 962-3 |

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| |4.Shimetani N, Shimetani K, Mori M. Levels of three inflammation markers, C-reactive protein, serum amyloid A protein and procalcitonin in the |

| |serum and cerebrospinal fluid of patients with |

| |meningitis. Scand J Clin Lab Invest 2001;61:567-74. |

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| |5. Hemavani N, Chitnis D, Joshi SP. C-reactive protein in CSF and its role in differential diagnosis of meningitis. Ind J Med Microb 2001;19:26-9. |

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| |6. R ajamani S. Estimation of C-reactive protein in serum and CSF for diagnosis of various meningitis. JAPI 2003;51:1279. |

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| |7.Kashyap RS, Kainthla RP, Mudaliar AV, Purohit GJ, Taori GM, Daginawala HF. Cerebrospinal fluid adenosine deaminase activity: a complimentary tool|

| |in the early diagnosis of tuberculous meningitis. Cerebrospinal fluid research 2006 March 30. |

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| |8.Gautam N, Aryal M, Bhatta N, BhattacharyaSK, Basal N, LAmsal M. Comparative study of cerebrospinal fluid Adenosine deaminase activity in patients|

| |with meningitis. |

| |Nepal Med Coll J 2007;9:104-6. |

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| |9. Chotmongkol V, Teerajetgul GY, Yodwut C. Cerebrospinal fluid adenosinedeaminase activity |

| |for the diagnosis of tuberculous meningitis in adults. Southeast Asian J Trop Med Public Health |

| |2006;37:948-52 |

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| |10. Choi SH, Kim YS, Bae IG, Chung JW, Lee MS, Kang JM, Ryu J, WooJH. The possible role of cerebrospinal fluid adenosine deaminase activity in the |

| |diagnosis of tuberculous meningitis in adults. Clin NeurolNeurosurg2002;104:10-5. |

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| |11.Vaishnavi C, Dhand UK, Dhand R, Agnihotri N, Ganguly NK. C-reactive proteins, immunoglobulin profile and mycobacterial antigens in cerebrospinal|

| |fluid of patients with pyogenic and nontuberculous meningitis. 1992;36:317-25. |

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| |12.Gerdes LU, Jorgensen PE, Nexo E, Wang P. C-reactive protein and bacterial meningitis: A meta-analysis. Scand J Clin Lab Invest 1998;58:383-93. |

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|9 |SIGNATURE OF CANDIDATE | |

|10 |REMARKS OF THE GUIDE |Clinical differentiation of Pyogenic and Tubercular and viral meningitis becomes difficult in|

| | |acute conditions. Cost effective, reliable and rapid diagnostic tests like CSF C-Reactive |

| | |protein and ADA level helps early diagnosis and initiation of treatment. Hence the present |

| | |study taken up. |

|11 |NAME AND DESIGNATION |Dr. NAGAPPA H HANDARGAL. MBBS, MD. |

| |11.1 GUIDE |PROFESSOR, DEPARTMENT OF MEDICINE, BMCRI, BANGALORE. |

| |SIGNATURE | |

| |11.3 HEAD OF THE DEPARTMENT |Dr. PRABHAKAR B. MBBS, MD. |

| | |PROFESSOR & HEAD, DEPARTMENT OF MEDICINE, BMCRI, BANGALORE. |

| |SIGNATURE | |

|12 |12.1 NAME OF DEAN AND DIRECTOR |PROF.DR.RAVIPRAKASH.D |

| | |DEAN AND DIRECTOR OF BANGALORE MEDICAL COLLAGE & RESEARCH INSTITUTE, BANGALORE |

| |12.2 SIGNATURE | |

| |12.3 REMARKS OF DEAN | |

ANNEXURE-I

INFORMED CONSENT

I, Mr. /Mrs. /Ms have been explained in a language well understood by me to my satisfaction about the study being carried out. I exercise my own free will power of choice and hereby give consent for myself being used as an object of, “A STUDY OF ESTIMATION OF CSF ADA AND CRP LEVEL IN DIFFERENTIAL DIAGNOSIS OF MENIGITIS IN ADULTS” conducted by Dr. Akkamahadevi v nipanal, Department of General Medicine , Victoria hospital/ Bowring and Lady Curzon hospital, Bangalore Medical College and Research Institute.The attending doctors have informed me about the purpose of study, the materials to be used during the course of the study as well as the complications associated with the methods/ tools to be used. I shall not hold the doctors or the staff responsible for any untoward consequences. I have no issues about sharing my details in case records and would co-operate for the study.I have been informed that I will not be sharing any incentives.I am also aware of my right to opt out of the study without prejudice to further treatment at any time during the course of study without having to give any reasons to do so. During the discussion with treating doctor at any time, there would be no compulsion to furnish any details and hence, the willingness to take part in the study is completely voluntary.

Signature of Doctor:

Signature/leftthumb impression of the Patient

Signature of the witness:

Date:

Place:

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