LITHUANIAN UNIVERSITY OF HEALTH SCIENCES
Department of Radiology
Review of volumetric brain assessment in
multiple sclerosis patients
Anastasia Bogachenko
Faculty of medicine VI
Group 38
Supervisor: Prof. Rymantė Gleiznienė, MD, PhD
Table of Contents
Summary ... 3 Conflict of interest ... 4 Abbreviations ... 4 Terms ... 5 Introduction ... 6Aim and Objectives ... 8
Materials and Methods ... 8
Literature review ... 9
Results and discussion ... 15
Conclusions ... 16
Summary
Author: Anastasia Bogachenko
Title: Review of volumetric brain assessment in multiple sclerosis patients
Introduction: Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system
Brain atrophy is a global marker of neuro-axonal loss resulting from demyelination and neuronal pathology. It is now known that brain atrophy occurs in all clinical stages of MS [1–4].
Aim: To review brain evaluation methods in MS patient from scientific literature. Objectives:
1. To provide an overview on brain measurement methods
2. To analyse the progression of brain atrophy in MS clinical subtypes
3. To investigate the Brain volume loss as a measure of disability progression in MS
4. To provide an overview on gray and white matter lesions in multiple sclerosis
Methods:
Systematic review that analyzed and compared research work and publication in the last 10 years in the English language. Using The Medline (PubMed) electronic research engine and including exclusion and inclusion criteria. The PRISMA guidelines were followed to carry out this review.
Results:
In this study analysis and comparison of articles from the last 10 years was done in order to present the latest development in the field of volumetric brain assessment in MS patients. A total of 41 clinical trials from 2179 were identified and used to write this review after implementing inclusion and exclusion criteria. The results showed that brain volume loss is accelerated compared to the general population. Through the years a broad variety of techniques for assessing global atrophy have been developed. In MS atrophy corresponds with a declining disability in patients
Conclusions:
Despite differences between people and techniques, there is a faster decrease in brain volume each year in MS patients. In comparison, the estimated reduction rate for healthy controls is slower.
In MS, all stages of the disease from CIS diagnosis through advanced progressive stages develop accelerated atrophy in the brain.
The MR imaging-based parameter correlates with disability and cognitive impairment development and predicts them better than focal lesions.
NAWM and NAGM on MRI, both contributed to a progressive loss of brain volume
Conflict of interest
I declare that there is no conflict of interest.
Abbreviations
BBSI-brain boundary shift integral
BICCR-brain to intracranial capacity ratio BPF-brain parenchymal fraction
SIENAX-structural image evaluation, using normalization, of atrophy-Cross-Sectional VBM-voxel-based morphometry
MS-Multiple sclerosis CNS-central nervous system BBB-blood brain barrier
MRI-magnetic resonance imaging GM-gray matter
WM-white matter
BET-brain extraction tool
SIENA-Structural Image Evaluation, Using Normalization, of Atrophy DMT-disease modifying therapies
CIS-clinically isolated syndrome RRMS-relapsing Remitting MS SPMS-secondary progressive MS CI-cognitive impairment
EDSS-Expanded Disability Status Scale PPMS-Primary progressive MS
MTR-magnetization transfer ratio DTI-diffusion tensor imaging
NAGM –normal appearing gray matter NAWM-normal appearing white matter TDS-template-driven segmentation method SABRE-semiautomatic brain region extraction
Terms
The McDonald criteria are diagnostic criteria for MS:
McDonald criteria for dissemination in space- Dissemination in space is defined as the development of lesions in distinct anatomic locations within the central nervous system, indicating a multifocal process. The McDonald criteria for dissemination in space are fulfilled if one of the following is present in a patient with a clinically isolated syndrome or typical MS attack:
An MRI with one or more hyperintense T2 lesions that are characteristic of multiple sclerosis in at least two of four MS-typical regions of the central nervous system:
o Periventricular
o Cortical or juxtacortical o Infratentorial
o Spinal cord
Development of an additional clinical attack characteristic of multiple sclerosis, supported by objective clinical evidence, which implicates a different central nervous system site.
McDonald criteria for dissemination in time- Dissemination in time requires the development or appearance of new central nervous system lesions over time. The McDonald criteria for dissemination in time are fulfilled if one of the following is present in a patient with a clinically isolated syndrome or a characteristic MS attack:
The development of an additional clinical attack, supported by objective clinical evidence, that is characteristic of multiple sclerosis
An MRI of the brain and/or spinal cord with the simultaneous presence of gadolinium-enhancing and nonenhancing lesions at any time, or by a new hyperintense T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan
Finding of cerebrospinal fluid-specific oligoclonal bands (as a substitute for dissemination in time).
Expanded disability status scale and functional systems:
The Expanded Disability Status Scale (EDSS) -is a method of quantifying disability in multiple sclerosis and monitoring changes in the level of disability over time. It is widely used in clinical trials and in the assessment of people with MS. The scale was developed by a neurologist called John Kurtzke in 1983 as an advance from his previous 10 step Disability Status Scale (DSS).
The EDSS scale ranges from 0 to 10 in 0.5 unit increments that represent higher levels of disability. Scoring is based on an examination by a neurologist.
Introduction
Multiple sclerosis is most common inflammatory and neurodegenerative autoimmune disease of the central nervous system (CNS) characterized by demyelination and axonal degeneration. Patients suffer from neurological symptoms disseminated in space and time, affecting recognize locations and occurring over multiple episodes. MS presents as an acute focal inflammatory demyelination and axonal loss with insufficient remyelination, resulting in chronic multifocal sclerotic plaques. The incidence peaks at 30 years old and the prevalence peaks at 50 [6–8].
Oligodendrocytes are the principal targets of immune attack in multiple sclerosis. The MS plaque is believed to be the result of a violation of the blood-brain barrier (BBB) caused by the upregulation of the adhesion molecules on the brain and spinal cord endothelium, which enables leukocytes to cross the walls of the vessel. They interact with myelin antigens and cause inflammatory demyelination when T cells enter the CNS. This reaction results in increased macrophage and microglial activity, leading to loss of the complex oligodendrocyte /myelin complex and eventually causing axonal injury. B cells also enter the CNS due to the weakness of the BBB. They produce both IgM and IgG immunoglobulin antibodies, resulting in oligoclonal bands that can be observed on agarose gel
electrophoresis along with an elevated IgG index. It is unclear to what antigen these antibodies are produced [9].
Diagnosis of MS may be established on its own on clinical basis or by imaging in addition to clinical evidence. Symptoms must last more than 24 hours per occurrence and manifest in discrete events separated by 1 month or more [10].
The presentations of the disease vary greatly, ranging from mild findings to rapidly evolving disease progression. Patients may have symptoms due to secondary one monofocal single central nervous system lesion or have symptoms secondary to multifocal lesions in two or more separate regions of the central nervous system. Such signs can be monophasic with a single occurrence, multiphasic with a relapsing type, or progressive [8].
The patient complains are: blurred vision, color desaturation, periorbital pain with eye movement, visual blurring during a hot shower or with physical exertion and generalized fatigue. Sensory symptoms in MS range greatly from paresthesias, including bladder dysfunction and tingling or prickling sensations or severe burning. Cognitive dysfunction is common, usually with impaired attention, difficulty shifting between tasks, and slowed information processing [10].
The latest up-to-date 2010 McDonald Guidelines explain the requirements for dissemination in time and space and make it easier to diagnose MS from the baseline brain MRI if both silent gadolinium- enhancing lesions and non-enhancing lesions are found on the same imaging. There are a variety of MRI based methods, including cross- sectional and longitudinal techniques, for evaluating global or regional brain volume. MRI is regularly used for treatment decisions, for recognition of subclinical disease and for predicting the progression of MS in a patient. Diagnosis of MS is more complicated at an early stage of the disease, as symptoms occurring across time and space are missing and the condition continues to progress without occasional exacerbations [5,11–13].
There is currently no treatment for MS, the therapy is categorized into a two-pronged approach: disease-modifying medications and symptom management. Life expectancy in the MS population is decreased by 7-14 years compared to the healthy [8,14].
This thesis aims to evaluate and provide an updated review on the methods developed to measure brain atrophy and analyze the progression of brain atrophy in clinically isolated syndromes also to investigate brain volume loss as a measure of disability progression and provide an overview on gray and white matter lesions in MS. Although major studies have reported atrophy of the optic nerve and spinal cord in MS, this study will concentrate on brain atrophy.
Aim and Objectives
Aim: To review brain evaluation methods in MS patient from scientific literature. Objectives:
1. To provide an overview on brain measurement methods
2. To analyse the progression of brain atrophy in MS clinical subtypes
3. To investigate the Brain volume loss as a measure of disability progression in MS
4. To provide an overview on gray and white matter lesions in multiple sclerosis
Materials and Methods
Data collection and search strategy:
In this systematic review PRISMA 2009 statement and check list were used as the main resource for research methodology. The main search engine was MEDLINE PubMed that yielded about 2179 research works. Randomized clinical trials, retrospective studies, systematic and literature reviews were used. Inclusion and exclusion criteria navigated which works should or shouldn’t be used.
Information source:
MEDLINE PubMed online research engine
Inclusion criteria:
Terms used: multiple sclerosis, MRI, atrophy, disability, cerebral atrophy, lesion load, cognitive
dysfunction, brain parenchymal volume, structural image evaluation using normalization of atrophy, lesions, normal-appearing white matter, grey matter.
Exclusion criteria:
Research work that wasn’t published in the last 10 years.
Works written not in the English language
Not relevant title or abstract
Data collection process:
The initial search in PubMed yielded 2179 results, which were reduced to 67 after using filters such as published in the last ten years, only English language, duplicate removal and abstract screen. In addition, articles were searched by hand using reference lists of other relevant articles on volumetric brain
67 Full text articles assessed for eligibility
41 Studies included in systematic review
assessment in multiple sclerosis. After full review of the text 41 research works were included into this systematic review.
Figure 1. Flow diagram of searching method
Literature review
Overview of brain measurement methods.
Demyelinating and neurodegenerative mechanisms in MS lead to the depletion of brain volume through the disease. Brain volume can be accurately assessed using magnetic resonance imaging (MRI) - based approaches to evaluate global or local brain volume, track changes in brain volume over time, or evaluate therapeutic response. How ever, when analyzing data on brain volume, the impact of various
26 not meeting inclusion criteria fully 625 Records screened
558 records excluded based on exclusion criteria (language, animal study, older than 10 years)
625 Records after duplicates removed
5 additional records identified by manual search of reference list of other publications.
2179 Records identified through database searching
confounding factors needs to be taken into account. These include MS-related, MS-unrelated and technicalfactors [13,15].
The current MRI-based approaches for evaluating brain volume split into two broad categories: cross- sectional or longitudinal:
1. Cross-Sectional Methods- Such techniques need a single image as input to assess the current state of atrophy. Generally, they are focused on brain tissue segmentation. The first of these methods to global brain atrophy measurement focuses on the estimation of the brain parenchymal fraction (BPF). This is the percentage of intracranial volume to brain volume If follow up scans of the same patient are obtained volume changes can be quantified and indices of changes can be made to the baseline scan [16]. BICCR is a method that is close to BPF but includes the brain to intracranial capability ratio (BICCR), segmentation of brain tissue as a primary stage. The volume of brain tissue is determined with respect to the volume of the inner table of the skull.
Other method uses a fuzzy "connectedness" algorithm for the segmentation and estimation of gray matter (GM), white [17,18]. Structural Image Evaluation, using Normalization of Atrophy-Cross- Sectional (SIENAX) Uses a completely automated algorithm to assess total brain volume measurements, WM and GM.. An automatic brain extraction tool (BET) is used to separate non- brain brains and to assess the outer surface of the skull.
Voxel-based morphometry (VBM) is a completely automatic whole-brain technique, enables for accurate cross-section and longitudinal analysis of local differences in tissue ‘‘concentration’’ between subject groups from structural imaging. Using this technique, the images are recorded in a database and statistical methods are used to make group comparisons over the entire brain without segmentation [19].
Another method defined by Alfano and the template-driven segmentation method (TDS) are additional methods for calculating brain volumes in different brain compartments. In a method by Alfano, volumes of GM, WM, and CSF are measured using a multispectral MR technique obtained with an unsupervised, automated brain segmentation. For TDS the description of the init ial signal intensity-based statistical tissue is gradually refined using a digital brain atlas as an anatomic template. This template, which is subdivided into over 120 anatomical tags, is linked to an image of a given subject using a variety of linear and nonlinear automated registration algorithms. Likewise, a newer technique (SABRE) offers a semiautomatic brain region extraction and uses individualized Talairach brain maps to demarcate and quantify particular brain regions in each hemisphere for each subject [20–22].
2. Longitudinal methods like Brain Boundary Shift Integral (BBSI) and SIENA (Structural Image Evaluation, Using Normalization, of Atrophy) assess changes in brain volume over time by comparing two sets of MRI scans obtained at various time points. Several cross-sectional methods (e.g. BPF) can also be used in longitudinal analyses to establish changes in brain volume over time [13].
The BBSI is a semi-automatic measure of the global cerebral atrophy rates of serial MRI imaging images. Using differences in voxel intensities, BBSI estimates changes in brain volume between 2 series of MR imaging volume scans in the boundary area of the brain. BBSI suggests that variations between recorded scans along the borders of cerebral structures are mainly due to the shifting of adjacent tissues. The SIENA method is another progressively common approach to directly assessing total brain volume changes. The method which includes 2 segmentation stages: the brain extraction tool and the FMRIB Software Library Automated Segmentation Tool (http:/www.fmrib.ox.ac.uk/fsl). This method analyzes changes in brain volume by evaluating precisely the local shifts in brain edge throughout the entire [17,23].
Overall, techniques based on segmentation are well adapted for cross-sectional pathophysiological studies, but are less reliable for quantification of longitudinal atrophy than techniques based on registration. The collected results between techniques usually cannot be compared directly. BPF and SIENA are the most widely used methods for evaluating brain volume in MS trials of DMTs and clinical [13,23].
Brain atrophy in MS clinical subtypes:
1. Clinically isolated syndrome (CIS) -This is the first clinical appearance of a disorder that displays the features of inflammatory demyelination that could be MS but has not yet met the criteria for dissemination in time. Loss in brain volume has been found in patients with CIS from the earliest stage of the disease. It has been documented that 60-80% of CIS suggestive MS patients and visible brain lesions on MRI develop clinically defined MS. in CIS patients Brain atrophy has been assessed using the SIENA method [13,19,24,25].
According to Dalton et al. [26] a 3 year follow-up of 58 CIS subjects showed that ventricular volume grew by 17.9% in 31 subjects who had acquired MS, while a 2.3% growth was reported in 27 subjects who remained healthy. In another study of 31 participants with a follow-up period of just 4-6 months, a
–0.27% reduction in brain volume was detected [27].
2. Relapsing Remitting MS (RRMS) -is the most common type of MS. Women are more affected by the disease. It is characterized by exacerbation of previous symptoms or the development of new ones. Upon relapse, the completely or partially recovery period continues for some time. Brain atrophy has been well established in relapsing multiple remitting sclerosis, which tends to develop quickly in the early stages of the disease [3,10].
In a study measured brain parenchymal volume in 53 patients with early untreated relapsing-remitting MS (disease duration 1–5 years) and recorded an average volume reduction of 2.7% over 2 years period. Another study of the mean atrophy rate in 34 individuals, evaluated using SIENA, showed a -0.7% year decline in brain volume over one year. Generally, the rate of brain-parenchymal volume loss in relapsing-remitting MS is 0.6–1.35% per year [28–30].
3. Secondary progressive MS (SPMS) -is a continuation to chronic relapsing/ remitting MS. It is characterized by a progressive deterioration of symptoms between relapses [10].
Studies that analyzed all patients with relapsing remitting MS and those with secondary progressive MS, reported similar annual rates of atrophy for the two categories, with levels for 0.6 and 0.8% per year. Some findings also found that brain atrophy has developed at a smaller rate in secondary-progressive MS than in relapsing MS, indicating that the more severe levels of atrophy occur early in the course of the disease, correspond with a fast accumulation of lesion [28].
4. Primary progressive MS (PPMS) -is characterized by a slow progression of the disease without remission periods. Both genders tend to be similarly affected, with the most frequent ages are between the late 30s and early 40s. The development of the disease is more common in the spinal cord and is less likely to affect cognitive function than other types [10].
While a few longitudinal studies have studied atrophy in PPMS, cross-sectional analyzes have demonstrated decreased brain volumes in PPMS compared to controls. Two longitudinal analyzes of 137 and 100 PPMS patients reported a reduction in central cortical volume of –1.0% year and- 1.3% year, respectively. A rate of –1.7% was found during the second year of follow-up in the previous study [19].
Brain volume loss as a measure of disability progression in MS
The most convincing reason for evaluating atrophy is because it provides a measure of axonal loss and, if progressive, is likely to result in permanent disability. An observation that about half of the normal white matter mass consists of axons suggests that severe atrophy in MS does indicate
axonal/neuronal loss. This conclusion is backed by the major associations found between atrophy and other axonal/neuronal MR markers. Never-the less the depletion of myelin, glial and vascular elements can contribute. Besides, astrocytosis and other inflammatory cells can add to the tissue mass, and changes in brain water due to inflammation, therapeutic effects or other intercurrent causes can also affect brain volume measurements [28].
Physical disability:
Lesion-load measures on MRI are poorly correlated with physical disability in cross-sectional studies, leading to the conventional "clinical imaging paradox" of MS. Lesions may show on MRI without the worsening of physical disability and, conversely, patients may worsen in disabilities without the presence of new lesions. Whole-brain atrophy has a greater, yet mild, imaging correlation with physical disability, and is a better indicator of future disability than T2-hyperintense and T1-hypointense lesion load [2,28]. Many groups tested the association between whole-brain atrophy and the EDSS score. EDSS has become a commonly accepted measure of clinical disability in patients with MS which can provide valuable information about the patients' medical condition. There are a few limitations with using EDSS alone as an outcome measure. The first, EDSS based on neurological examination, which is subjective. Also, the clinical state of the patient may not reflect the true activity of MS in the CNS. Such factors may restrict the use of EDSS as a separate measure. Along with MRI volumetric scales, the use of the EDSS score provides a reliable correlation between radiological appearance and clinical condition and offers the main feature of MS functional impairments [33].
One research found that the rate of deterioration of brain atrophy over 18 months was substantially elevated in patients with declining of disability, whereas only trends were observed between disability change and development of T2-hyperintense lesions [34]. Early atrophy appears to foresee the eventual occurrence of physical impairment to a greater degree than the lesion-load measure.
A longitudinal study showed that patients with a higher disability 8 years later had more atrophy in the first 2 years. Additionally, the change in the brain parenchymal fraction during the first two years has been the greatest MRI indicator for eight years of disability after taking into account the 2-year change in all MRI-lesion measurements. At 8 years, patients with the greatest volume of brain atrophy were nearly four times more likely to have a disability level requiring walking aid or worse.
As a consequence, brain atrophy is emerging as a clinically significant indicator of MS disease progress, reinforced by its association with a physical disability [25,28].
In about 50% of MS patients, cognitive impairment is observed. There have been several studies that have shown a correlation between cognitive impairment (CI) and a loss of brain volume. Additionally, several groups documented that early deterioration of brain volume may be indicative of longer-term cognitive changes, possibly offering a sensitive marker of deteriorating cognitive function in RRMS [13,19].
According to Rao SM et al. [31] an early study reported a correlation between cognition and third ventricular width. The correlation between brain atrophy and neurobehavioral status has been confirmed by multiple subsequent studies. In another research by Dalton CM et al. [37] has shown significantly greater ventricular enlargement within one year in individuals who develop MS in comparison to those who remain stable.
By brain atrophy and neuropsychological impairment studies, we can assume that subcortical atrophy is linked strongly with a disturbance in general cognitive dysfunction, which can be explained with the disruption of frontal-subcortical circuits. Regional or cortical atrophy assessments can provide an insight into impairment in a variety of patients with more specific functional domains [28].
Gray and white matter lesions in multiple sclerosis
The classic characteristic of MS are the Focal lesions. MS lesions are typically circular or ovoid and vary in size from a few mm to more than 1 cm in addition they contain various degrees of inflammation, axonal injury, gliosis and demyelination. On T1-weighted images, some of these lesions are seen as isointense to hypointense in compared to GM [1,38,39].
Irregularities in the normal-appearing white matter (NAWM) described as WM without noticeable lesions on routine MRI, have been regularly documented on quantitative MRI in patients with MS, and these irregularities display a mild overall association with histopathological changes, like myelin and axon loss. The anomalies can be found by T1 relaxation time mapping, magnetization transfer ratio (MTR), diffusion tensor imaging (DTI), and spectroscopy are clinically important and have a prognostic value [40].
In MS, gray matter demyelination can be very significant, especially in the disease's chronic phase. Abnormalities of 'normal-appearing' gray matter (NAGM) could be observed in patients with MS using a range of quantitative MRI measures, including DTI, MTR, T1 relaxation time mapping and MRS .Various forms of lesions have been identified according to their site within the GM. It is poorly known what causes these lesions, many pathogenic mechanisms are being tested. Focal cortical lesions are
usually not seen on standard MRI scans because they are small and contrast poorly with the normal gray matter surrounding it, and it may contribute to some of the quantitative MRI changes observed in the NAGM [39,40].
According to M. Calabrese et al. [41] studies have found that in those with early relapsing-remitting MS and those with progressive disease types, new cortical lesions continue to develop during 1–2 years of follow-up.
Significant changes in normal-appearing WM and GM are correlated with progressive brain volume loss. As a result, the reduction of brain volume in MS happens in early and all disease stages and subtypes in both the WM and GM [1].
Results and discussion
In this systematic review I analyzed and compared different research works done in the last ten year in order to present the most updated information about volumetric brain assessment in MS patients. This review of published papers has yielded 41 studies on the methods developed to measure brain atrophy and analyse the progression of brain atrophy in clinically isolated syndromes also to investigate brain volume loss as a measure of disability progression in MS patient and provide an overview on gray and white matter lesions in multiple sclerosis. Sample sizes in all studies were generally small ranging from 30 to 160 patients. The follow up lasted from 1 year till 8 years, with the majority of cases were followed for 2 years. The main outcome is that for MS patients, brain volume loss is accelerated compared to the general population, starting early and lasting throughout the disease [13].
Currently, MRI measures of brain atrophy are our best present measure of neuronal, particularly their axonal degeneration in MS. A broad variety of techniques for assessing global atrophy have been developed and shown to be sensitive to changes from the early beginning of the disease to later progression stages. As a result brain atrophy provides a better clinical disability marker than conventional lesion measures [13,19,28].
Looking at the results of studies evaluating the progressive cerebral atrophy in individual patients with MS by serial MRI scanning. The findings indicate that atrophy corresponds with a declining disability, and while it could be present in patients without measurably increased disability, it is progressing at a far slower rate than in those who do [13,11,24,28].
Regional brain atrophy measures may be particularly helpful in trying to understand neuro- psychological dysfunction or other specific clinical findings. Consideration must be provided to confounding factors in determining whether the reduction of brain volume specifically suggests tissue atrophy [11,19,25,28].
Multimodal MRI techniques incorporating atrophy, DTI, MTR and MRS for separate classes of tissue may help to explain the relative donations to pathogenic GM and WM processes [34-35].
Conclusions
Several conclusions could be drawn from the research done in volumetric brain assessment in multiple sclerosis patients those results:
Despite differences between people and techniques, there is a faster decrease in brain volume each year in MS patients, in comparison to healthy controls..
In MS, all stages of the disease from CIS diagnosis through advanced progressive stages develop accelerated atrophy in the brain.
The MR imaging-based parameter correlates with disability and cognitive impairment development and predicts them better than focal lesions.
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