INTRODUCTION
1.1 -Overview of Multiple Sclerosis(MS)
Multiple sclerosis or (MS) (from Latin: sclerosis
- scarring) is an autoimmune and
neurodegenerative condition wherein
inflammations occur in the central nervous
system (CNS). White matter axons,
oligodendrocytes, and glial cells are
progressively damaged. This process involves
various injuries in the nerve axis, myelin sheath,
and gliosis. It can involve both the CNS and the
spinal cord and is classified as a
neurodegenerative disorder (Figure 1-1). It is
exceptionally widespread as a preventive cause of
permanent disability among the younger
population, predominantly affecting individuals
during their productive years (ages 20-45).
Figure 1-1 Normal neuron with a Myelin vs Demyelination in MS with damaged
Myelin. [Link]
It is estimated that 2.5 million MS patients are spread around the
globe. They suffer from signs and symptoms that vary depending on
the extent and the sites of nerve damage, which are frequently
interconnected. One of the untreated manifestations has the potential
to engender more such conditions, which cumulatively influence the
quality of life of the patient.
Such causes are the inflammatory plaques disintegrating nerve cells,
which largely cause the symptoms. However, late-stage symptoms are
more persistent. Common initial symptoms of MS include optic
neuritis, sensory disturbances, and weakness, which are the major
clinical features that help significantly in diagnosis
(Figure 1-2).
gure 1-2. Common initial symptoms of MS. (National Multiple Sclerosis Society.
Multiple Sclerosis:
[Link]
Figure 1-2. Common initial symptoms of MS. (National Multiple Sclerosis Society.
Multiple Sclerosis: [Link]
Throughout the progression of the illness, the majority will
experience loss of mobility, 80%, and fatigue, 70% but also loss of
cognitive function, sexual function, bowel and bladder control,
together with loss of coordination
1.2 Classification of the Types of
MS
Relapsing-remitting MS (RRMS) accounts for 85% of MS patients.
RRMS is a sequence of remission phases (stability) and relapse or
exacerbation. The chronic progressive form of MS is divided into primary
progressive MS (PPMS), secondary progressive MS (SPMS), and
progressive relapsing MS (PRMS) (refer to Figure 1-3). However, the new
classification by Lublin aims to distinguish progressive disease types
according to their clinical and MRI activity. About two-thirds of patients
diagnosed with RRMS may develop into SPMS, which can be defined as
an initial period of relapsing-remitting followed by gradual neurological
worsening. PPMS is characterized by slowly progressive disability from
onset, marked by localized subpial inflammation without blood-brain
barrier disruption.
Figure 1-3. The course of MS is highly varied and heterogeneous. The disease is characterized initially by episodes of reversible clinically isolated
neurological deficits, which is often followed by progressive neurological deterioration over time.
Activity is defined as the presence of clinical relapse or presence of new plaques over time either on T2 scan or T1 contrast enhanced MRI scans
6.
1.3 Pathophysiology of MS
The exact pathophysiological mechanism of this neuro-degenerative
disorder and loss of
function is still not clear, although there are great advances in the
scope of treatment for MS.
Genetic predisposition and activation of the immune system by
environmental factors are
thought to initiate the disease
. Most regions identified in large genome wide associated studies
indicate T cell activation as the major factor in developing the
disease
. The combination of
lower genetic tolerance to environmental factors like Epstein-Barr
virus (EBV), HIV-6
(Herpesvirus 6), HRTLV and Chlamydia Pneumoniae as well as UV
exposure, diet and
smoking most likely trigger the onset of disease
1.4 Management of MS
The management of MS patients is divided into prophylactic
immunomodulatory therapy and symptom management (such as
spasticity, bladder dysfunction, fatigue, depression, anxiety, etc.). Disease-
modifying therapy can reduce the relapse rate and delay the progression of
disability. It consists of both short-term and long-term treatments.
Relapses are typically treated acutely with high-dose intravenous
methylprednisolone (MP) at doses ranging from 500 to 1000 mg over 3 to
5 days. Long-term treatment aims to suppress the self-proliferation of
immune cells. Currently, there are 11 MS treatments approved by the
TGA, all demonstrating evidence of slowing the progression of disability
in patients. For instance, ABC treatments (Avonex, Betaferon, and
Copaxone) are considered first-line therapies in most countries and are
administered as subcutaneous or intramuscular injections.
Recently, oral treatments such as Fingolimod (Gilenya), Teriflunomide
(Aubagio), and dimethyl fumarate (Tecfidera) have been introduced, all
acting to reduce the circulating lymphocyte count. More potent therapies
like Natalizumab (Tysabri) and Alemtuzumab (Lemtrada) are given as
infusions and carry a high risk of secondary infections or autoimmune
diseases. Treatment efficacy is usually monitored by assessing the
annualized relapse rate (ARR), changes in the expanded disability status
scale (EDSS), as well as activity on MRI.
1.5 Limitations of Conventional MRI
Methods and the Role of MRS
Patients diagnosed with multiple sclerosis (MS) often rely on T2
lesion load observed in MRI to meet the McDonald criteria. However,
they frequently require additional testing to confirm their diagnosis,
as routine MRI is not specific for MS and only detects approximately
60% of newly forming lesions. Furthermore, MRI findings do not
correlate well with the Expanded Disability Status Scale (EDSS).
Conventional MRI techniques are also insensitive to axonal loss,
gliosis, and demyelination processes. Despite the lack of better
options, MRI remains a key tool not only for diagnosis but also for
clinical management and therapeutic decision-making.
Consequently, monitoring disease activity through annual imaging is
considered best practice.
To enhance the sensitivity and specificity of detecting ongoing MS
activity, advanced MRI techniques are indicated. One such
technique is Magnetic Resonance Spectroscopy (MRS), a non-
invasive method that identifies and quantifies metabolites in vivo,
providing chemical information instead of anatomical details. MRS
measurements are obtained from a localized voxel in a specific brain
region, making the voxel's location crucial. Notably, there are
significant differences in neurometabolites between gray and white
matter, as well as between lesions and normal-appearing white
matter (NAWM). In clinical practice, MRS techniques have been
employed to assess the neurometabolic changes in the MS brain
(figure 1_4) ,
facilitating the identification of critical biochemical alterations.
Figure
Figure1-5
1-4 .The neurometabolic changes of the MS.