Rajiv Gandhi University of Health Sciences



RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA BANGALORE

ANNEXURE – II

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

|1 |Name of the Candidate |Dr. SINDU P. GOWDAR |

| |and Address |D/O PRAKASH GOWDAR |

| |(in Block Letters) |#3087, 9TH MAIN, 3RD CROSS, |

| | |M.C.C ‘B’ BLOCK |

| | |DAVANGERE, 577004 |

| | |KARNATAKA. |

|2 |Name of the Institution |J.J.M. MEDICAL COLLEGE, |

| | |DAVANGERE – 577 004. |

|3 |Course of the Study and Subject |POSTGRADUATE |

| | |M.D. IN RADIO-DIAGNOSIS |

|4 |Date of Admission to Course |1ST JUNE 2012 |

|5 |Title of the Topic |“MR EVALUATION OF WHITE MATTER DISEASES” |

|6. |BRIEF RESUME OF THE INTENDED WORK: |

| |Need for the study: |

| |Virtually all categories of pathology may cause white matter abnormalities. White matter abnormalities may be seen in congenital, |

| |inflammatory, neoplastic, post traumatic, metabolic, toxic, vascular, degenerative and demyelinating diseases. The primary white matter|

| |disorders are classically divided into two groups dysmyelinating disorders (usually metabolic), in which normal myelin fails to form, |

| |and the demyelinating diseases, in which normal myelin has formed and is later destroyed by a myelinoclastic process. Adult |

| |leukoencephalopathies (and white matter disorders which are not age-specific) may be caused by several categories of disease. Primary |

| |demyelinating disorders, infectious, neoplastic, post-traumatic and metabolic disorders are the most common. When white matter disease |

| |is encountered on an imaging study, it is useful to first characterize the white matter involvement as multifocal, confluent / diffuse,|

| |or selective (geographic). This approach, combined with the clinical information regarding patient demographics, clinical history and |

| |physical findings, helps the imager limit the differential diagnosis.1 |

| |Pediatric white matter diseases are divided into four categories based on high-intensity abnormalities seen on long TA images and |

| |correlative clinical information: demyelinating disease, dysmyelinating disease, developmental delay (of myelination), and white matter|

| |abnormalities of unknown origin. The last group of pediatric white matter diseases is those of unknown origin. It is in this group that|

| |perhaps MR had its greatest impact in lesion-detection capabilities.2 |

| |The advent of MR has revolutionized the concept of understanding of white matter diseases. MRI is considered far superior to CT and the|

| |imaging modality of choice in white matter diseases. However, with the advent of multiecho sequences of MR, even subtle lesions of |

| |demyelination can be detected. A correct diagnosis could be made in majority of the patients based on MR findings and clinical history |

| |alone. MR, in conjunction with clinical findings, plays a significant role in establishing the diagnosis and in the further follow up |

| |of patients with white matter diseases.3 |

| |MRI will play a key role in the diagnostic evaluation of MS in children. Application of more advanced MRI techniques such as MR |

| |spectroscopy (MRS), magnetization transfer (MT), and diffusion tensor (DT) imaging yield more tissue-specific insights into |

| |neuro-axonal and white matter integrity than conventional MRI assessment.4 |

| |The difference in water diffusion, namely anisotropic versus isotropic diffusion, between gray and white matter, can be used to |

| |selectively highlight the white matter tracts and to assess their integrity. Hence, it has been postulated that diffusion- weighted MR |

| |imaging would be a useful tool to monitor the development of the normal brain. Children with dysmyelination or demyelination of white |

| |matter, diffusion-weighted MR imaging provides information that is not apparent on conventional T1- or T2-weighted MR images. Diffusion|

| |restriction precedes brain myelination and is further increased during myelination.5 |

| |The newly emerging field of axonal fiber tracking from DTI data 43, 44 may have a major impact on our understanding of the clinical |

| |manifestations of degenerative and inflammatory disease processes. Not only can a primary site of axonal injury be determined with DTI,|

| |but it may be that Wallerian degeneration45 and perhaps even axonal pathways underpinning cortical remodeling could be visualized.6 |

| |A number of inborn errors of metabolism result in neurological disorders that are associated with white matter abnormalities. MRS can |

| |provide more specific information than MRI and can help in the diagnosis of many of these diseases.7 |

| |Review of literature: |

| |MRI features of 116 children enrolled in the French cohort of acute CNS demyelination by B. Banwell, MD et al, found that MRI criteria |

| |specific for pediatric-onset multiple sclerosis (MS) and criteria predictive of MS outcome in children experiencing a first |

| |demyelinating event will be challenged by the overlap in MRI features between acute monophasic demyelinating syndromes and MS, |

| |particularly in younger children. Emergence of new clinically silent lesions on MRI scans separated by at least 3 months is |

| |characteristic of MS. Newer MRI techniques evaluating white matter biochemistry and integrity in the youngest MS patients may provide |

| |new insights into the relative contributions of inflammation and neurodegeneration in MS.4 |

| |In a study of MR evaluation of white matter diseases by BN Lakhkar, M Aggarwal, JR John it was concluded that MRI due to its excellent |

| |gray-white matter resolution is very sensitive in detecting subtle demyelination, the sensitivity being still further enhanced by FLAIR|

| |sequences. The present study concludes that MRI, in correlation with the clinical signs and symptoms is an ideal modality in early |

| |diagnosis of white matter diseases and aids in the early institution of therapy so that the curable conditions among them can be |

| |treated.3 |

| |MR imaging performed by Engelbrecht, MD et al, in 101 of the 173 children revealed a broad variety of pathologic changes. This study |

| |concluded that during early brain myelination, diffusion restriction in normal white matter increases. Anisotropy precedes myelination |

| |changes that are visible at MR imaging. Compared with T1- and T2-weighted MR imaging, diffusion-weighted MR imaging in white matter |

| |diseases reveals additional information.5 |

| |Whole-brain voxel-wise investigation of both grey matter topography and white matter integrity (Fractional Anisotropy) were carried out|

| |on 25 adolescent-onset schizophrenic patients and 25 healthy adolescents by Douaud G et al. There was a widespread reduction of |

| |anisotropy in the white matter, especially in the corpus callosum. We speculate that the anisotropy changes relate to the functional |

| |changes in brain connectivity that are thought to play a central role in the clinical expression of the disease. We found striking |

| |abnormalities in the primary sensorimotor and premotor cortices and in white matter tracts susbserving motor control (mainly the |

| |pyramidal tract). This novel finding suggests a new potential marker of altered white matter maturation specific to adolescent-onset |

| |schizophrenia.8 |

| |A study was done on 14 (11 male, three female) patients with a DSM-IV diagnosis of schizophrenia (n¼7) or schizoaffective disorder |

| |(n¼7) as determined by the Structured Clinical Interview for the DSM-IV by A. Ardekani et al. Using a rigorous voxelwise analysis, |

| |they have demonstrated reductions in WM integrity in patients with schizophrenia or schizoaffective disorder compared to healthy |

| |control subjects. The regional distribution of these differences is consistent with other reported structural brain abnormalities in |

| |schizophrenia. By assessing differences in WM integrity across the whole brain, this method can inform hypothesis-driven studies of WM |

| |integrity in schizophrenia as well as other disorders of the brain.9 |

| |In a study done by van der Voorn, MD et al, Forty-one patients (19 male, 22 female; mean age, 15.4 years) and 41 control subjects (25 |

| |male, 16 female; mean age, 11.3 years) were included. Twelve patients had a hypomyelinating disorder; 14 had a demyelinating disorder;|

| |five had a disorder characterized by myelin vacuolation; and 10 had a disorder characterized by cystic degeneration. It was concluded |

| |that quantitative MR techniques can be used to discriminate between different types of white matter disorders and to classify white |

| |matter lesions of unknown origin with respect to underlying pathologic conditions.10 |

| |In a recent systemic review with meta-analysis on incidental findings in brain magnetic resonance imaging by Morris et al, it was found|

| |that neoplastic incidental brain findings had a prevalence of 0.7% (135 of 19559 people out of 16 studies) with increased prevalence |

| |with age. The non-neoplastic incidental findings were even more prevalent at 2.0% (375 of 15559 in 15 studies). The overall prevalence |

| |of incidental brain findings on MRI was 2.7 %, equivalent to one for every 37 subjects scanned.11 |

| |In a study by de Leeuw FE et al, a total of 1077 subjects aged between 60–90 years were randomly sampled from the general population. |

| |Of all subjects 8% were completely free of subcortical white matter lesions, 20% had no periventricular white matter lesions, and 5% |

| |had no white matter lesions in either of these locations. It was concluded that the prevalence and the degree of cerebral white matter |

| |lesions increased with age. Women tended to have a higher degree of white matter lesions than men. This may underlie the finding of a |

| |higher incidence of dementia in women than in men, particularly at later age.12 |

| |In a study by Tourbah A et al, fifty six patients among whom 39 had white matter diseases had MRI of the brain comparing FLAIR sequence|

| |to a conventional proton density sequence. Flair sequence allowed to detect 18 additional hypersignal (HS) that were not present on T2 |

| |sequence. These HS were located in the periventricular areas for 5 of them, near the cortical sulci in 10, and in the centrum |

| |semi-ovale for 3. FLAIR sequence permitted analyze 41 other lesions that were not obvious on proton density sequences. Thirty five of |

| |them were thus confirmed to be HS : 31 in the paracortical areas, 3 in the paraventricular regions and one in the internal capsule, |

| |whereas the remaining 6 were normal sulci of the brain. FLAIR sequence increases the sensitivity of MRI in white matter diseases.13 |

| |In a study by Kjos BO et al, seventy-six children with developmental retardation of unknown cause underwent MR imaging of the brain. |

| |Twenty-one (28%) had positive MR findings, including nine with atrophy, six with delayed myelination, four with multiple focal white |

| |matter lesions, three with hypoplastic white matter, and three with migration abnormalities. The frequency of abnormality was highest |

| |in nonautistic children with associated neurologic physical findings (61%) but was also significant in nonautistic children without |

| |neurologic findings (23%). They concluded that MR will reveal brain abnormalities in about one third of nonautistic children with |

| |developmental retardation of unknown cause, and more often in those with neurologic deficits, seizures, or a small head size.14 |

| |In their study, Filippi M. et al compared a fast fluid-attenuated inversion recovery (fast-FLAIR) sequence to conventional spin-echo |

| |(CSE) in the evaluation of brain MRI lesion loads of seven patients with clinically definite multiple sclerosis. Four hundred and two |

| |lesions were detected in at least one of the two sequences: 128 were seen only on fast-FLAIR, 17 only on CSE. 41 lesions were larger on|

| |fast-FLAIR, while no lesion was considered larger on CSE. The numbers of periventricular (P = 0.05), cortical/subcortical (P = 0.02) |

| |and discrete (P = 0.05) lesions detected using fast-FLAIR were higher than those detected using CSE. The data indicates that fast-FLAIR|

| |sequences are more sensitive than CSE in detecting multiple sclerosis lesion burden and that fast-FLAIR is a promising technique for |

| |natural history studies and clinical trials in multiple sclerosis.15 |

| |Because demyelinating disease of the brain occasionally presents with large ring-enhancing lesions on computed tomography (CT) scans |

| |and magnetic resonance images (MRIs), Masdeu JC et al, sought to determine whether the ring pattern differed from that found in other |

| |common brain lesions with ring enhancement. The observers rated the contrast enhancement pattern as (1) open ring, with enhancement in |

| |the border of the lesion abutting the white matter; (2) closed ring; or (3) uncertain. For all diagnostically certain cases (n = 112), |

| |inter-rater agreement was excellent (kappa = 0.75). As an average of the two reviewers, scans for 11 of 132 cases were read as |

| |uncertain; 89% of adrenoleukodystrophy cases, 41% of the multiple sclerosis cases, 3% of tumors, and 9% of infections were classified |

| |as having the open-ring pattern. Overall, 66% of demyelinating lesions had an open-ring pattern compared with 7% of the |

| |non-demyelinating lesions (chi2 = 41.2, p < 0.0001). An open-ring pattern of enhancement is more likely to be associated with |

| |demyelinating lesions than with nondemyelinating lesions.16 |

| |Objective of the study: |

| |To evaluate the role of magnetic resonance imaging in white matter diseases |

| |To establish an accurate diagnosis and to narrow down the differential diagnosis in various white matter diseases |

| |To assess the severity and extent of the underlying lesion in various conditions of white matter diseases. |

| |To demonstrate the different patterns of abnormal myelination in white matter diseases. |

|7. |MATERIALS AND METHOD |

| |Source of data |

| |The main source of data for the study is patients from the following teaching hospital attached to Bapuji Education Association, J.J.M.|

| |Medical College, Davangere. |

| |Bapuji Hospital |

| |Chigateri General Hospital |

| |Women and child health care hospital. |

| |Appropriate MR sequences and multiplanar imaging will be performed for every patient. |

| |Technique: |

| |Imaging will be done with 1.5 Tesla Philips Achieva Machine using Sense Head coils. The following sequences will be selected as |

| |required. |

| |Localizer sequence conventional spin echo. |

| |Sagittal FLAIR, STIR, T1 FS |

| |Axial and sagittal T1 images |

| |Axial, sagittal and coronal T2 images |

| |Proton density images. |

| |Diffusion weighted imaging and ADC map |

| |Axial Grey matter only and white matter only sequences |

| |OPTIONAL SEQUENCES: |

| |DTI and FT; IV contrast study; TOF angiography shall be included in the study as and when required. |

| |Method of collection of Data (including sampling procedures if any) |

| |All patients referred to the department of Radio diagnosis with clinical history suspicious of white matter diseases in a period of 2 |

| |years from October 2012 to October 2014 will be subjected for the study. |

| |Initially a minimum of 30 cases are intended to be taken up, however it may be extended up to 50 cases depending upon the availability |

| |of cases within the study period. |

| |Inclusion criteria: |

| |Patients with clinical suspicion of white matter diseases. |

| |Incidental finding of white matter diseases/ lesions. |

| |Patients of all age groups. |

| |Exclusion criteria: |

| |The study will exclude |

| |Patients with clinical suspicion of post-traumatic white matter injury. |

| |Patients with Intracranial tumors and metastatic disease. |

| |Patients having history of claustrophobia. |

| |Patient having history of metallic implants insertion, cardiac pacemakers and metallic foreign body in situ. |

| |Duration of study: 2 years |

| |Data Analysis: Proportion study |

| | |

| |Does the study require any investigations or interventions to be conducted on patients or other humans or animals? If so please |

| |describe briefly. |

| |Yes |

| |The study is mainly based on investigations as radiology itself is a tool of investigation. The study involves only humans. Informed |

| |consent would be taken after explaining about and before any procedure. Routine investigations, laboratory investigations, |

| |ultrasonogram and CT would be done as and when required. |

| |Has ethical clearance been obtained from your institution in case of 7.3? |

| |Yes |

| |Ethical clearance has been obtained from the Research and Dissertation Committee/Ethical Committee of the institution for this study. |

|8. |LIST OF REFERENCE: |

| |Blake A. Johnson. Practical approach to white matter diseases. Advanced MRI 2002- from head to toe. 2002 |

| |Martha A. Nowell, Robert I. Grossman, David B. Hackney, Robert A. Zimmerman, Herbert I. Goldberg, Larissa T. Bilaniuk. MR Imaging of |

| |White Matter Diseases. 1988 August AJR 151:359-365, August 1988 0361 -803X/88/1 51 2-0359. |

| |Lakhkar BN, Aggarwal M, John JR. MRI in white matter diseases - clinico radiological correlation. Indian J Radiol Imaging [serial |

| |online] 2002 [cited 2012 Oct 4]; 12:43-50. |

| |Banwell, B, Shroff, M, Ness, JM, et al. MRI features of pediatric multiple sclerosis. Neurology 2007; 68(Suppl. 2):S46–S53. |

| |Engelbrecht V, Scherer A, Rassek M, et al (2002) Diffusion-weighted MR imaging in the brain in children: findings in the normal brain |

| |and in the brain with white matter diseases. Radiology 222: 410–418 |

| |Mark A. Horsfield, Derek K. Jones. Applications of diffusion-weighted and diffusion tensor MRI to white matter diseases – a review. 5 |

| |DEC 2002 |

| |Janet Cochrane Miller, July 2012 – Volume 10, Issue 7 |

| |Douaud, G., Smith, S., Jenkinson, M., Behrens, T., Johansen-Berg, H., Vickers, J., James, S., Voets, N., Watkins, K., Matthews, P., and|

| |James, A. (2007). Anatomically-related grey and white matter abnormalities in adolescent-onset schizophrenia. Brain, 130:2375–2386. |

| |Ardekani BA, Nierenberg J, Hoptman MJ, Javitt DC, Lim KO. MRI study of white matter diffusion anisotropy in schizophrenia. Neuroreport |

| |2003;14(16):2025–9. |

| |van der Voorn JP, Pouwels PJ, Hart AA, Serrarens J, Willemsen MA, Kremer HP, Barkhof F, van der Knaap MS (2006) Childhood white matter |

| |disorders: quantitative MR imaging and spectroscopy. Radiology 241:510–517 |

| |Cheng. Magnetic Resonance Imaging study of brain and incidental finding of white matter hyperintensities and microbleeds. Medical |

| |Bulletin; 2011 Feb vol 16 No.2 |

| |De Leeuw FE, de Groot JC, Achten E.  et al.  Prevalence of cerebral white matter lesions in elderly people: a population based magnetic|

| |resonance imaging study: the Rotterdam Scan Study.  J Neurol Neurosurg Psychiatry.2001; 70:9-14. |

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| |Tourbah A, Deschamps R, Stievenart JL, Lopez A, Zizen IMT, Caen LO et al. Magnetic resonance imaging using FLAIR pulse sequence in |

| |white matter disease. Neuroradiology 1996; 23(4): 217-222 |

| |Kjos BO, Umansky R, Barkovich AJ. MR of the brain in children with developmental retardation of unknown cause. AJNR 1990; 11: 1035-1040|

| |M. Filippi, C. Baratti, T. Yousry, M. A. Horsfield, S. Mammi, C. Becker, R. Voltz, S. Spuler, A. Campi, M. F. Reiser, and G. Comi . |

| |Quantitative assessment of MRI lesion load in multiple sclerosis: A comparison of conventional spin-echo with fast fluid attenuated |

| |inversion recovery. Brain (1996) 119(4): 1349-1355 doi:10.1093/brain/119.4.1349 |

| |Masdeu JC, Moreira J, Trasi S, Visintainer P, Cavaliere R, Grundman M. The open ring. A new imaging sign in demyelinating disease. J |

| |Neuroimaging 1996; 6: 104–7. |

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|9 |Signature of Candidate | |

|10 |Remarks of the Guide |The study is viable and helps in management of patients of all age groups at |

| | |an early stage. |

|11 |Name and Designation of | |

| |(in block letters) | |

| |11.1 Guide |Dr. NAVEEN S. MARALIHALLI MD |

| | |ASSOCIATE PROFESSOR |

| | |DEPARTMENT OF RADIO-DIAGNOSIS, |

| | |J.J.M. MEDICAL COLLEGE, |

| | |DAVANGERE – 577 004. |

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| |11.2 Signature | |

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| |11.3 Co-Guide (if any) |--- |

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| |11.4 Signature |--- |

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| |11.5 Head of Department |Dr. J .PRAMOD SETTY MD |

| | |PROFESSOR AND HEAD, |

| | |DEPARTMENT OF RADIO-DIAGNOSIS, |

| | |J.J.M. MEDICAL COLLEGE, |

| | |DAVANGERE – 577 004. |

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| |11.6 Signature | |

|12 |12.1 Remarks of the Chairman and Principal | |

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| |12.2 Signature | |

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