Inflammatory Disorders in the Brain and CNS

NL Sicotte, Cedars Sinai Medical Center, Los Angeles, CA, USA

B Renner, Cedars Sinai, Los Angeles, CA, USA

Glossary
Autoimmune disease Diseases that arise from abnormal
immune response within the body against normally
occurring cells and tissues. The etiologies are relatively
unknown, though genetic susceptibility is largely suspected,
along with exogenous triggers such as bacteria, virus, drugs,
and chemical and environmental irritants.
CADASIL Cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy, the most
common form of hereditary stroke disorder; it is understood
to be caused by mutations in the Notch 3 gene on
chromosome 19, which plays a key role in neuronal
development. Affected populations are usually between 40
and 50 years of age with onset clinical manifestations of
migraines, strokes, and ultimately dementia.
Cortical lesions Abnormalities in the tissue of the cortex;
various factors can lead to lesions such as traumatic brain
injury, vascular disorder, and tumors.
Demyelination The progressive deterioration of the myelin
sheath of a neuron, due to cell death or lack of progenitor
cells. This ultimately leads to impaired conduction of
potentials down the axon causing deficiencies in movement,
cognition, and sensation.
Diffusion tensor imaging A technique of magnetic
resonance imaging (MRI) that measures the restricted
diffusion of water in the tissue, such as in white matter,
which produces tractography of the neurons. Each acquired
voxel has the parameters of diffusion rate and direction in
three-dimensional space that allows for the measurement of
the diffusion profile, leading to calculated conclusions
about the thickness and length of a white matter tract.
Functional MRI A technique of MRI that measures temporal
brain activity by detected changes in blood flow. Blood
oxygenation level-dependent imaging shows relative activity
of a brain region due to the oxygenationdeoxygenation of
the tissues, leading to a small magnetic field that can be
detected by MRI.
Multiple sclerosis A chronic, typically progressive disease
involving damage to the myelin sheaths of the central
nervous system nerve cells; impaired transduction of

Central Nervous System Inflammatory Diseases

Inflammatory disorders of the brain and central nervous
system (CNS) encompass a huge number of conditions, a
detailed discussion of which is beyond the scope of this
article. In general, these represent an important group of disorders that frequently affect otherwise healthy adults and can
lead to significant morbidity and long-term disability. Noninvasive neuroimaging techniques, in particular magnetic

Brain Mapping: An Encyclopedic Reference

neuronal signals leads to disruption in communication of

the areas of the CNS. As the disease progresses, lesions of
plaque form in the white matter of the CNS. The mechanism
for disease is unknown, though thought to be a failure of the
myelin-producing cells due to immunodeficiency or genetic
predisposition spurred by environmental factors.
Myelin A dielectric layer formed around the axon of a
neuron essential for proper transduction of signals. In the
CNS, oligodendrocytes produce the layer composed of 80%
lipid and 20% protein. It allows for action potentials to
more rapidly propagate down the length of the neuron than
unmyelinated axons due to decreased capacitance across the
cell membrane and increased electrical resistance that
prevents the current from leaving the axon.
Neuromyelitis optica (NMO) A heterogeneous condition
consisting of inflammation and demyelination of the optic
nerve and spinal cord. Though the mechanism is similar to
multiple sclerosis, brain lesions are distinct. The main causes
of NMO are proposed to be autoantibodies to aquaporin 4,
which conducts water through cell membrane.
Oligodendrocyte A type of neuroglial cell that provides
support and insulation to axons in the CNS by creating the
myelin sheath. It can extend its processes to up to 50 cells. A
satellite oligodendrocyte serves to regulate the extracellular
fluid surrounding neurons that allows for proper ionchannel conduction in action potentials.
Progressive multifocal leukoencephalopathy A severe viral
disease characterized by progressive damage and
inflammation of the white matter of the brain. Most affected
by the disease are those with severe immunodeficiency. It is
due to the JC virus, which is normally present, but kept in
check due to functional immune response. The progression
of the disease leads to the degradation of the myelin sheath
surrounding the CNS neurons by destroying
oligodendrocytes.
Sarcoidosis A disease involving the abnormal collection of
inflammatory cells that form nodules in multiple organs. In
neurosarcoidosis, cranial nerves and myelopathy can occur.
The etiology is due to immune reaction to infection or other
antigen.

resonance imaging (MRI), have played an important role in

advancing our understanding of CNS inflammatory disorders.
These roles include the use of MRI to establish a diagnosis,
frequently earlier in the disease course than is possible using
clinical criteria. In addition, MR metrics have been utilized as
pivotal biomarkers in testing new therapeutics and are used in
routine clinical practice to monitor disease progression and
response to therapy. Beyond these functions though, imaging
studies using traditional and novel measures have advanced

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our understanding of the pathophysiology of CNS inflammatory disorders leading to important new insights into the disease process. As we move into the era of cell-based therapies
and other advanced approaches, novel multimodal imaging
techniques will be increasingly central to these efforts.
Currently, there is an urgent need to develop more targeted
imaging biomarkers that capture not only inflammation but
also the neurodegenerative changes that frequently accompany
CNS inflammatory disorders.

Differential Diagnoses
Inflammatory disorders include those with infectious, postinfectious, autoimmune, neoplastic, and genetic etiologies
(see Table 1). Autoimmune disorders include multiple
sclerosis (MS), acute disseminated encephalomyelitis
(ADEM), and other less common variants. There are several
disorders that lead to changes seen on MR imaging of the brain
and spinal cord. Diagnosis is typically made on the basis of
clinical presentation and specific imaging findings including
the presence of areas demonstrating enhancement after the
administration of contrast material. In MRI studies, the contrast used is gadolinium-based (Gd). This is a paramagnetic
substance that appears as a bright signal on T1-weighted MRIs.
Acute inflammation in the CNS is associated with a breakdown
of the bloodbrain barrier leading to the extravasation of the
contrast material into the parenchyma. The presence of areas
with Gd enhancement is useful for helping to establish a
diagnosis of CNS inflammation and to time the relative age
of lesions detected. In the case of ADEM versus MS, this can be
very helpful (Figure 1).
Table 1

Diagnosis
MRI criteria play a key role in establishing the diagnosis of all
of these disorders, but no more so than that for MS. Previously,
diagnosis depended on establishing the presence of clinical
symptoms over time (i.e., multiple episodes) and space (multiple locations within the CNS). This process depended on
obtaining reliable histories and detailed neurological exams
and could take as long as 5 years between initial symptoms
and verification of the diagnosis. During the era before effective therapeutics were available, this lag in making a diagnosis
was not critical, but all that has changed with the introduction
of disease-modifying treatments for MS. The timely initiation
of MS treatments has been associated with better long-term
outcomes as well. The currently utilized diagnostic criteria
require the demonstration of dissemination in time (DIT)
and dissemination in space (DIS), but this can be established
using MRI scans after the onset of a single clinical event
(Polman et al., 2011). The presence of both enhancing and
nonenhancing brain or spinal cord lesions can satisfy both DIT
and DIS when detected after a typical MS event such as optic
neuritis (Rovira et al., 2009). The widespread availability of
MRI has led to the identification of a new entity termed radiologically isolated syndrome (Okuda et al., 2009), which could
be considered a pre-MS condition, in which an individual
demonstrates characteristic changes on MRI in the absence of
any symptoms or neurological dysfunction. Monitoring of
these at-risk individuals has shown that the majority go on to
have either clinical events or new radiological activity (Okuda
et al., 2014). Examples of MRI findings in MS and associated
disorders can be found in http://radiopaedia.org/articles/multiple-sclerosis.

Inflammatory disorders of the brain and spinal cord

Syndrome

Imaging findings

Notes

Acute disseminated
encephalomyelitis
(ADEM)
Behcets disease

Large lesions with mass effect; all lesions show contrast

enhancement

Postinfectious or postvaccination; more common in children

Monophasic (Javed and Khan, 2014)

Diffuse white matter changes; venous sinus thrombosis

CADASIL

Lesions in the temporal poles, external capsules, insula, and

U-fibers

Lymphoma
Multiple sclerosis

Involves the basal ganglia; contrast-enhancing

White matter lesions in periventricular, juxtacortical, brain
stem, and spinal cord regions
Presence of enhancing lesions associated with relapses,
atrophy of gray matter/cortex detectable early
Longitudinally extensive spinal cord inflammation with mass
effect, bilateral optic neuritis, lesions in brain stem,
hypothalamus, and area postrema
leukoencephalopathy

Clinical triad: uveitis, oral ulcers, and genital ulcers

Small vessel vasculitis
Silk Road disease
Cerebral autosomal dominant arteriopathy with subcortical
infarcts and leukoencephalopathy, caused by mutations in
Notch 3, on chromosome 19
Seen in immunocompetent and immunocompromised hosts
More common in young women of northern European
heritage, autoimmune demyelinating disease, relapsing and
progressive forms of the disease exist

Neuromyelitis optica

Progressive
multifocal
Opportunistic
infection occurs in
Sarcoidosis
Susacs syndrome
Vasculitis

Biomarker is NMO-IgG, detected in serum; binds to aquaporin

4; water channel found throughout the CNS (Jurynczyk
et al., 2014; Muto et al., 2014; Ying et al., 2014)
Large juxtacortical white matter lesions, with progressive
enlargement

immunocompromised host, caused by JC virus

Longitudinally extensive spinal cord changes, brain stem
lesions, persistent contrast enhancement
Gray and white matter lesions, brain infarcts
Cortical infarcts, juxtacortical lesions, microhemorrhages

More common in people of African descent, noncaseating

granulomas
Retinal infarcts, hearing loss, and encephalopathy
Seen in a variety of autoimmune disorders

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NE

DA

Relapses
Unreported relapses
Clinical activity

Clinical disease progression

Subclinical relapses: focal MRI activity
am
age

Focal MRI activity

En
d-o
rga
nd

Focal gray and white matter lesions

not detected by MRI
Brain atrophy

Hidden focal and diffuse MRI activity

Spinal fluid neurofilament levels

Biomarkers
Microscopic or biochemical pathology

Figure 1 Pyramid from NEDA to end-organ damage. http://multiple-sclerosis-research.blogspot.com/2014/09/clinicspeak-ms-phenotypes-by-mri.

html.

Monitoring Disease
Serial MRI scanning is done frequently to monitor disease progression and response to therapy. The interpretation of these
scans is complicated by the lack of standardized imaging protocols and variations in slice orientation or slice thickness.
Thinner, nongapped scans are needed to accurately and reliably
detect changes in lesion activity. The Consortium of Multiple
Sclerosis Centers (CMSC) has developed guidelines for initial
and follow-up MRI acquisition (see initial publication of Simon
et al. (2006) and on their website http://c.ymcdn.com/sites/
www.mscare.org/resource/collection/9C5F19B9-3489-48B0A54B-623A1ECEE07B/mriprotocol2009.pdf). Although developed for MS, these principles are equally important as
applied to any progressive CNS disorder.
In the era of more than ten FDA-approved MS therapies
(and growing), determining when a particular agent is a
failure has taken new importance. Based on studies done on
MS patients treated with interferon beta preparations, there is
evidence that the presence of any new inflammatory activity
and/or clinical activity (new relapse) predicts the development
of long-term disability (Sormani et al., 2013). This has led to
the notion of achieving a state of no evident disease activity or
NEDA as a goal of disease-modifying therapy in MS (see http://
multiple-sclerosis-research.blogspot.com/2013/12/neda-treat2-target-and-las-vegas.html). The determination of no evident
disease activity or a disease-free state requires the acquisition
of accurate serial MRIs.

Hidden Disease
Although the hallmark of MS is the presence of white matter
lesions, the disease is now known to affect both deep gray matter

structures and the cerebral and cerebellar cortices (Damasceno

et al., 2014). The use of higher field strengths and routine FLAIR
imaging led to the discovery of widespread cortical demyelination. These cortical lesions likely play a key role in the progression of clinical disability in MS but were unrecognized until
recently. Furthermore, they are hard to detect on standard MRI
acquisitions and do not demonstrate contrast enhancement.
The effect of the currently approved therapies on the accumulation of cortical lesions has not been reliably determined yet, in
part due to the factors mentioned in the preceding text. Newer
techniques such as phase-sensitive MRI can lead to better detection of cortical lesions but is most sensitive at ultrahigh field
strengths of 7 T (Sethi et al., 2012).
In addition to cortical demyelination, other less obvious
changes occur in MS and other CNS inflammatory disorders,
including an acceleration of the overall brain atrophy and
selective vulnerability of deep gray matter structures. In particular, the thalamus (Houtchens et al., 2007) and hippocampus
(Papadopoulos et al., 2009; Sicotte et al., 2008) show changes
that have been associated with fatigue and cognitive impairment in MS. Furthermore, functional abnormalities, as measured by functional MRI (fMRI), have been demonstrated to
occur early in the course of MS and to progress in association
with disease severity (Ernst et al., 2014). This underscores the
fact that MS, and likely other inflammatory CNS disorders, can
be characterized as a neurodegenerative disease, sharing similarities with Parkinsons disease and Alzheimers disease.
Newer, multimodal imaging techniques that utilize tractspecific structural and functional imaging approaches such as
combined diffusion tensor imaging and fMRI are promising
techniques to better capture the widespread and dynamic
nature of brain changes in these disorders (Koenig et al.,
2014; Rocca et al., 2014; Figure 2).

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Figure 2 The lesions in the deep white matter (yellow arrow) are
nonspecific and can be seen in many diseases. Typical for MS in this case
is the involvement of the temporal lobe (red arrow); juxtacortical
lesions (green arrow), touching the cortex; involvement of the corpus
callosum (blue arrow); and periventricular lesions, touching the
ventricles.

The Future
The next era of imaging approaches to study MS and other
disorders will focus on detecting and monitoring demyelination or remyelination status (Mallik et al., 2014), and these
approaches include magnetization transfer imaging, quantitative magnetization transfer, myelin water fraction imaging
(Shen et al., 2013), diffusion tensor imaging metrics, and
positron emission tomography imaging of myelin. In addition,
techniques are currently under development to track and monitor stem cell transplants including oligodendrocyte progenitor
cells that could be used to remyelinate axon and potentially
restore function (Douvaras et al., 2014). These and other novel
approaches attract researchers and donors alike (http://mymsaa.org/PDFs/MSAA_Research_Update_2014.pdf).

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Relevant Websites
http://emedicine.medscape.com/article/1146199-differential DDx on MS vs other
CNS inflammatory disease.
http://www.mstrust.org.uk/atoz/edss.jsp EDSS Scale.
http://multiple-sclerosis-research.blogspot.com/2014/09/clinicspeak-ms-phenotypesby-mri.html.
http://www.mymsaa.org/about-ms/treatments/long-term/ 11 approved FDA
treatments.
http://www.mymsaa.org/publications/msresearch-update-2014 2014 Review on MS
research and treatment (http://mymsaa.org/PDFs/MSAA_Research_Update_2014.
pdf).
http://www.nationalmssociety.org/What-is-MS/Who-Gets-MS Stats, such as total
patients with MS.
http://neuropathology-web.org/chapter6/chapter6aMs.html Good MS resources.
https://neurowiki2012.wikispaces.com/StemCelltherapyforMultipleSclerosis
Stem cell therapy in MS, many figures.
http://www.radiologyassistant.nl/en/p4556dea65db62/multiple-sclerosis.html
Comparison of MRI images between MS and other inflammatory CNS disease.
http://radiopaedia.org/articles/multiple-sclerosis Case presentation of MS lesions.