OPEN ACCESS
Multiple sclerosis: a review
Cristiano Farace1, Consolación Melguizo2, Yolanda Asara1, Pablo Álvarez2, José Prados2, Paola Tolu2,
Giuseppe Delogu1, Antonia Aránega2, Roberto Madeddu1,3*
1 Department of Biomedical Science - Histology, University of Sassari, Sassari, Italy; 2 Institute of Bio-pathology and Regenerative Medicine
(IBIMER), Department of Human Anatomy and Embryology, School of Medicine, University of Granada, Granada; 3 National Institute of
Biostructures and Biosystems (INBB) , Rome, Italy
Abstract
Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system (CNS) which
affects mostly aged between 20 and 40 years. MS causes demyelination of the white matter of the brain with this
process sometimes extending into the gray matter. The MS patients show white matter with areas of damage name
plaques or lesions. The progressive loss of myelin, a lipoprotein that covers the axon of neurons, inhibits the
coordinated and rapid transmission of nerve impulses causing various symptoms that characterize all demyelinating
diseases in general and MS in particular. MS is a disease not clinically well characterized since it is unpredictable.
The type and severity of symptoms can vary greatly according to the affected CNS areas and the extent of the
damage. Recent studies show that the biochemical aspect of the lesions may vary between the different MS forms.
However, this is not the predominant reason why patients with MS differ in their symptoms.
Citation: Farace C, Melguizo C, Asara Y, Álvarez P, Prados P, Tolu P, Delogu G, Aránega A, Madeddu R. Multiple sclerosis: a review. MedMol
Research Reports 2011; e3: 16-23. doi: 10.4428/MMRR.a.201104001
Published March 10, 2011
Copyright: © 2011 Farace et al. This is an open-access article which permits unrestricted use, distribution, and reproduction in any medium,
provided the original author and source are credited.
Competing Interests: The authors have declared that no competing interests exist.
Keywords: multiple sclerosis; central nervous system; demyelination
* E-mail: [email protected].
progressive MS (PP-MS). This form of MS is characterized by a
progressive disease without remitting periods. However, brief
periods of disease activity cessation (periods of stability) may
be detected. The PP-MS differs from RR-MS and MS-SP since
the onset of the disease is found mostly in the patient's age
between 30 and 45, in both men as in women [7]. Moreover, the
initial damage is usually to the spinal cord rather that of the
brain. 4) Progressive relapsing MS (SM-RP). This form of MS
has a progressive course since onset, punctuated by remitting
periods. Moreover, although a significant recovery after a
period of relapse may be detected, a worsening between
relapses are always observed. Fortunately, this form of MS is
the least common [4].
An alternative way of EM classification is divided into benign
MS, malignant SM and transitional/progressive SM. MS is
considered a subset of SM-RR forms of MS in which the course
the disease is fast with a very severe disability in a relatively
short period of time. Fortunately, the malignant form of MS is
extremely rare. Finally, the SM transitional/progressive is
characterized by a course in some years with isolated attack
(Devic's disease). The NMO is a physical condition related to
MS that is characterized by an attack of optic neuritis in both
eyes followed by severe inflammation of the spinal cord
(Transverse Myelopathy). The Balo's concentric sclerosis is a
rare condition that clinically it is difficult to distinguish of MS.
Forms of Multiple Sclerosis
The course of disease can not be established at the time of
diagnosis, even on the basis of medical history [1], clinical
criteria or neuroradiology [2,3]. The disease classification is
based on follow-up after diagnosis (fig.1).
In order to standardize the terminology of the clinical course
of MS subtypes, members of the international community MS
research [3] identified the following four forms of MS: 1)
Relapsing/remitting MS (RR-MS). This form is characterized
by recurrence or exacerbation of old symptoms and/or
appearance of new symptoms. Relapses are followed by periods
in which patient recovers completely or partially neurologic
deficits. Relapses can last for days, weeks or even months and
recovery may be gradual or instantaneous. Typically, the MSRR is found in patients of age between 20 and 30. The
incidence of this form is double in women than in men [4]. 2)
Secondary progressive MS (SP-SM). This form is characterized
by a gradual worsening of the disease. As with RR-MS cases,
SM-SP form has periods of relapse and remitting. However,
except for rare cases of stable remitting, there is never a real
physical recovery. It has been demonstrated that 50% of RR-MS
patients with over 10 years of disease may evolve to a SM-SP
form [1,5]. After 25-30 years, this percentage increases to 90%.
The time average between the onset of the disease and the
conversion from MS-RR to SM-SP is 19 years [6]. 3) Primary
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However, magnetic resonance imaging shows Balo's lesions
that are characterized by alternating concentric circles and intact
myelin in areas where there is demyelination axons.
Magnetic resonance exploration shows that most plaques do
not produce recognizable symptoms ("silent"). It is not clear the
reason for this phenomenon, but it is possible that other parts of
the CNS may replace damaged neurons. The origin of the lesion
is not clear but there are many evidences on the involvement of
cells immune system, especially T helper lymphocytes, macrophages and mast cells (fig. 2).
These cells may segregate some signaling molecules cytokines and chemokines- which cause cellular destruction.
Besides damaging the myelin, the immune system attacks
oligodendrocytes, leading to a considerable delay the process of
remyelinization.
Multiple sclerosis “plaques”
MS lesions, also known as "plaques”, are areas inflamed CNS
in which neurons have lost their myelin. These lesions
distributes randomly in CNS white matter. Demyelinated
neurons do not function efficiently and cause the symptoms of
MS. The disease progression leads to damage of neuronal
axons. Glial cells are responsible for the repair of damaged
nerves, in particular oligodendrocytes and astrocytes.
Figure 1. Clinical forms course of the disease showing the level of disability patient in
relation to time (see text).
Epidemiological studies have yielded the following
conclusions: 1) the age group most affected by MS is between
the 20 and 50 years, in spite of MS may also occur in young
people (under 16) and seniors (over 70). 2) The MS appears
with higher frequencies above 40° of latitude. However, the
prevalence rates may differ significantly at the same
geographical area and at the same latitude and climate. 3) The
MS is more common in Caucasians than other ethnic groups,
but there was a high frequency also in the asian and hispanic
populations in Africa. 4) Migration between some geographical
areas may be a risk to develop the disease. Some studies have
shown that immigrants and their descendants may be a greater
risk level of MS. These studies show the complex relationships
between genetic and environment in determining who will
develop the disease. 5) The MS is at least 2 or 3 times more
common in women than men (which is a factor tending to
increase), suggesting that hormonal imbalances may be
involved in determining susceptibility to disease. 6) The genetic
factors certainly play a significant role in determining who
develops MS. In USA, one in every 750 may develop the
disease. In addition, children or siblings of SM patients, are a
Multiple sclerosis and epidemiology
To date, there are no definitive answers about the
epidemiology of MS. The non existence of a test to detect the
SM make the diagnosis partial, late or incorrect. It is very
difficult to estimate real impact of MS. Most epidemiologists
focus their attention to the prevalence of MS (and not the
incidence). The most reliable data are certainly coming northern
hemisphere.
Geographical distribution. Global distribution of MS is very
heterogeneous (Figure 3). A significantly higher incidence is
found in northern and southern latitudes in northern and
southern hemisphere, respectively. This observation is based on
the high incidence of disease Scandinavia, Northern USA and
Canada, Australia and New Zealand. The term "epidemy" of
MS emphasizes the importance of environmental factors as risk
factors of pathology. The most obvious fact about this is the
disease incidence in the Feroe islands after the occupation of
British troops in the second World War. Similar increase of the
incidence has been observed in Shetland Islands, Iceland and
Sardinia, but never has been identified the key factor.
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population with a higher risk of the disease (one in 100 or one
in 40).
SM incidence in Sardinia: an exceptional case.
Epidemiological studies showed a high and increasing rate of
frequency MS in Sardinia. Analyzed according to distribution
common territorial and linguistic domains, the results showed
an unexpected heterogeneity. As described in a recent study [8],
differences in prevalence of MS between different ethnic
subgroups residing in the same environment, supporting a
genetic predisposition underlying pathology, but on the other
hand, indicate that the of MS in Sardinia may not be simply
explained by a general predisposition. So, an environmental
factor may be strongly associated with pathology of MS.
Taking into account the genetic and linguistic differences, the
domain Gallura is very distant from the rest of the province of
Sassari. The frequency distribution of DNA haplogroups
indicates their mitochondrial DNA sequence is significantly
closer Corsica and Italy than the Sardinian hinterland [9].
Interestingly, Gallura has the lowest rate of MS throughout the
province of Sardinia [10,11]. Moreover, analyzing the data
according to the subdivision in common and linguistic domains,
the prevalence of MS has unexpected heterogeneity in the
province, with a gradient distribution of MS on the basis of
genetic (and linguistic) characteristics [12].
Figure 2. Plasma cells (derived from B cells after soluble antigens contact) release antibodies. These antibodies bind antigens such as the myelin of
neuron axons. Myelin is produced by oligodendrocytes. Now, antibodies can activate the complement cascade and/or inducing antibody-mediated
phagocytosis by macrophages. CD4+ T cells are activated by antigens presented by MHC II molecules on dendritic cells and microglial cells.
Cytokines and chemokines are released. Activated macrophages induce damage in neurons and oligodendrocytes. CD8+ T cells directly recognize
surface antigens presented on cells such as neurons and oligodendrocytes inducing a direct damage in these cells.
only in 35% of cases. In addition family studies show that some
genes such as the Major Histocompatibility Complex (HLA)
genes, may be related to MS origin [16]. In addition, IL2RA and
IL7RA genes [17] have been related with this pathology. The
HLA complex is directly involved in antigen presentation,
which is crucial for a proper functioning of the immune system,
whereas mutations in receptor genes for IL2 and IL7 were
related to diabetes and other autoimmune diseases, supporting
the autoimmune hypothesis of MS [16]. Among the genes
tissue-specific of the nervous system, the KIF1B gene (kinesin)
is the first that has been correlated with significant risk increase
of developing this disease [18]. Other studies have revealed
several genes mapped in chromosome 5 that appear to be related
Multiple sclerosis: etiology and emergence mechanisms
a) Environmental causes. Some studies have shown a
statistically significant association between the disease and the
presence of a large number of virus and bacteria, such as HTLV
1, Epstein-Barr virus, Human Herpes Virus 6, Chlamydia
pneumoniae and MSRV [13,14]. These agents would provide a
suitable ground for the development of an immune response
directed at the CNS myelin [15].
b) Genetic cause. The risk of acquiring the disease is higher in
family of the MS patients than in the general population,
especially in the case of siblings, parents and children.
Nevertheless, in the case of identical twins there is a correlation
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to MS [19]. The study of genomes of patients with MS appears
very relevant in this direction.
c) Diet, vitamins and other alternative. It has been suggested
that MS is the side effect of a diet unbalanced. Some diets have
been proposed as potential treatments for MS. In fact, some
patients have responded positively. A decrease in exposure to
sunlight (MS is more common in people who live farther
equator) has been associated with a higher risk of disease
[20,21]. The decreased production of vitamin D could explain
this correlation. Stress may also be a risk factor in MS [20]. In
contrast, cigarette smoking does not seem a risk factor.
Vaccinations have been considered as a possible factor risk
although most of the studies show a correlation not significant
between vaccines and MS [20]. Patients with MS have a lower
circulating level of uric acid compared with healthy subjects.
Uric acid could protect the body from oxidative stress by some
function substances such as peroxynitrite [22]. Finally, some
researchers consider that SM has multiple causes.
Figure 3. Geographical distribution of the disease indicating areas with high risk (red), probable high risk (yellow),
North-South gradient risk (blue) and low risk (grey).
natalizumab, has intended to prevent the entry of these cells in
CNS [24].
c) Autoimmunity. MS could be caused by the immune system
itself, becoming unable to distinguish antigens "self". A recent
study shows that rats infected with Mycobacterium tuberculosis
genetically modified develop an autoimmune response against
myelin. Expression of the myelin-like protein MPT64-PLP
proteolipid (PLP) was able to activate the cell-mediated
response with clonal expansion of T lymphocytes and
subsequent attack on the myelin [25].
Multiple sclerosis: pathological mechanisms
a) Inflammation and demyelination. Epidemiological studies
on MS have contributed positively to discovery of the possible
causes of the disease. The symptoms of MS are caused by an
abnormal inflammatory process in brain and spinal cord. This
could be a response caused by genetic factors, environmental
and viral infections, which promote axonal demyelination.
Demyelination is associated with a massive activation of the
immune system, activation of the humoral and cell-mediated
response, production of a large amount of T lymphocytes and
attack to the myelin. The damage to myelin leads to nerve fibers
sclerosis of the CNS. Glia is able to repair some of the injury
caused by inflammatory processes, but is unable to perform any
complete reparation. The exacerbation and remitting (very
common in MS) is the result of this alternate damage/repair.
b) Damage to the blood-brain barrier. The blood-brain barrier
is a protective barrier formed by glial cells to endothelial cells
that line the blood. This structure allows the exchange of
oxygen, essential nutrients, dioxide carbon and other molecules
between the blood and the CNS. If blood-brain barrier is altered,
pathogens can have access to encephalon as well as some
elements of the blood, including T lymphocytes, could get
trapped inside the brain inducing a abnormal inmunoreponse
against CNS [23]. An experimental therapy for MS treatment,
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Signs and symptoms of Multiple sclerosis
MS symptoms (table 1) usually appear during exacerbations
with a worsening of physical/mental health of the patient and a
progressive damage of the neurological functions [4]. Most
forms of MS have symptoms defined as "clinically isolated
syndrome” (CIS). CIS is a neurological episode of at least 24
hours and compatible with a CNS demyelinating disease. The
MS generally show sensory symptoms (46% of cases), visual
(33%), brain (30%) and motor symptoms (26%) [26]. Infrequent
Initial symptoms are aphasia and epilepsy [27-29]. Subclinical
MSis relatively common [30]. Patients can suffer from many
symptoms and neurological signs, including changes in
sensitivity (numbness and paraestesia), muscle spasms and
difficulty in movement [31], difficulties in coordination
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(ataxia), problems in the eye (nystagmus, optic neuritis, or
diplopia) [32], fatigue and acute or chronic pain [33] and
urinary incontinence [31,33,34], dysarthria and dysphagia [35].
Sometimes, MS is detected in patients with others neurological
consults.
Cognitive and/or emotional dysfunctions as depression and
instability humoral are very common [36,37]. The main
measure of clinical progression disability and severity of
symptoms is known as "Expanded Disability Status Scale”
(EDSS) [38]. The MS relapses are unpredictable. However,
recurrence, for example, appear more frequently in spring and
summer [39], in association with infections (influenza and
gastroenteritis) and with stress [40,41]. There is no s scientific
evidence for an increased risk due to vaccination (influenza,
hepatitis B, varicella, tetanus, tuberculosis) [42] or physical
injuries [43]. Higher temperatures may intensify symptoms
(phenomenon Uhtoff) [39].
Motor Symptoms
Visual Symptoms
Paresis
Paraplegia, hemiplegia, tetraplegia, quadraplegia
Hypotonia
Spasms, Clonus
Footdrop
Dysfunctional reflejes
Spasticty and muscle atrophy
Dysarthria
Diplopia
Nystagmus
Movement and sound phosphenes
Afferent Pupillary Defect
Ocular Dysmetria
Internuclear Ophthalmoplegia
Sensory Symptoms
Paraesthesia
Anaesthesia
Proprioceptive dysfunction
Neuralgia (Trigeminal neuralgia)
Neuropathic and neurogenic pain
Coordination and Balance Symptoms
Ataxia, Speech Ataxia
Intention tremor
Dysmetria
Vertigo
Dystonia, Dysdiadochokinesia
Bowel, Bladder and Sexual Symptoms
Frequent micturation, Bladder Spasticity
Flaccid Bladder, Detrusor-Sphincter Retrograde
ejaculation
Frigidity
Constipation
Dyssynergia
Erectile Dysfunction, Anorgasmy
Fecal Urgency, Fecal Incontinence
Cognitive Symptoms
Depression
Cognitive dysfuntion
Bipolar syndrome
Anxiety
Aphasia, Dysphasia
Dementia
Mood swings, emotional lability,
euphoria
Other Symptoms
Fatigue
Uhthor´s symptom
Gastroesophageal refflux
Sleeping Disorders
Table 1. Symptoms of SM
demyelinated increase of "free" water particles (rather than
"bound"). The diffusion tensor MRI (DT-MRI or DTI) record
the random motion of water molecules. The individual
molecules of water are in constant motion, induced by collision
with other water molecules at extremely high speeds. The DTMRI applied for the production of maps spread fairly intricate,
three-dimensional images that show the record size and location
of demyelinated areas of the brain. Changes in this process can
then be measured and correlated with disease progression.
Functional MRI (IRMf) uses radio waves and a strong field
magnetic to observe any correlation between physical changes
in brain (such as blood flow) and mental functioning during
performance of cognitive tests.
b) Cerebrospinal fluid (CSF) analysis. A small CSF amount is
useful to determine oligoclonal bands (an increase in the
number of specific antibodies) suggesting an excessive immune
activity in the fluid. This test is positive in 90% of patients, but
not is specific for MS. It frequently happens that CSF analysis
is not enough for definitive diagnosis of MS, but its results are
Diagnosis of Multiple sclerosis
MS Diagnosis is the result of a careful clinical history and a
neurological examination including magnetic resonance
imaging (MRI) and lumbar cerebrospinal fluid collection
(LCR). There is no single test to detect MS. In fact, a patient
whose symptoms and clinical course suggest MS should be
examined for other possible disorders.
a) Magnetic Resonance (MR). Imaging technologies can
identify “plaques” in CNS. It is often used in combination with
gadolinium (contrast), which helps to differential diagnosis.
However, lesions may occur in other neurological disorders, so
their presence is not absolute diagnostic for MS. Resonance
spectroscopy magnetic (RMS) provides information on returns
biochemical brain quantifying the concentration of N-acetyl
aspartate. The decrease in this acid concentration is inversely
proportional to nerve damage. The magnetic transfer imaging
(MTI) is able to detect white matter abnormalities, quantifying
the water "free" in tissues. The damaged nerve tissues show a
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useful to exclude other pathologies. The number of white blood
cells in the CSF of MS patients is up (seven times) higher than
normal. In MS, the antibodies cross the blood-brain barrier and
attack the myelin. Consequently, the level of antibodies in the
CSF of a person with MS is much higher than normal.
c) Biological markers in CSF. In the last years the
investigation about new biomarkers which are able to diagnostic
EM is a new way in neurological research. A "biomarker" is a
molecule objectively quantified and evaluated as an indicator of
normal biological process, a process pathogenic or a
pharmacological response to an intervention therapy [44]. A
"clinical end-point" is a characteristic or variable that reflects
the patient health and possibly the life time remaining. One of
the objectives of biomarkers is to substitute “end point clinical”.
In the case of MS, biomarkers in CSF are useful in predicting
and monitor the onset and evolution of neurological damage in
affected people. So far, it has been determined a large amount
of markers in MS body fluids, including structural proteins,
enzymes and antibody.
Tubulins are globular proteins involved in the formation of
microtubules. This protein is essential for the cytoskeletal
proteins being involved in cell mitosis, and cytokinesis. Tubulin
is a dimer composed by α-tubulin and β- tubulin (molecular
weight about 55 kDa). To form microtubules, the dimers of αand β-tubulin bind to GTP [45]. The GTP molecule bound to βtubulin subunit is hydrolyzed to GDP through the inter-dimer
contacts along the protofilaments of microtubule[46]. When
bound to GTP or GDP of β-tubulin dimer influence the stability
of the dimer in microtubules. The β-tubulin exists in the form of
six isotypes in different cell mammals [47]: The β-tubulin class
I is the most common and was found in most tissues, the βtubulin class II was found in many tissues but primarily in the
brain and in Schwann cells, widely distributed neuronal axons
and in dendrites [48]. The synthesis of this molecule increases
in the regeneration and development of neurons [49].
Recent studies have shown that, in the development of the
human brain, may be an indicator of neural stem cells [48]. The
β-tubulin class III neuron-specific protein is abundant in the
CNS and PNS, where its expression is clearly visible during
fetal life and postnatal development. The distribution of βtubulin type III is associated with some neurons with
differential temporal and spatial gradients depending of the
neuroepithelial origin. The transient expression of this protein is
present in the subventricular zone of the CNS including cells
and/or glial precursor cells, as well as in Kulchitsky
neuroendocrine cells of fetal respiratory epithelium. This
expression temporally limited and potentially non neuronale
may have implications for identification neurons derived from
embryonic stem cells. The subtype β-tubulin III distribution is
neuron-specific in adult tissues and its expression increases
during axonal growth [50,51]. The protein is a neuron specific
marker in SN. It also appears in Sertoli cells of the rete testis
and in some neuronal origin tumors such as lymphomas,
carcinoma squamous cell carcinoma and malignant melanoma
[52]. The β-tubulin class IV exist as two subtypes that differ
from the others in the amino acid position; the β-tubulin IVa is
specific to the brain, while the β-tubulin IVb is ubiquitous; both
are constitutively expressed [49].
S100B protein and glial fibrillary acidic protein (GFAP)
are proteins unique to the glia. S100B protein is a cytosolic
protein found in astrocytes and oligodendrocytes. GFAP is the
main protein of glial intermediate filament [53]. The GFAP is a
type III protein specific to astrocytes of the CNS. However, it
has been detected in ependymomas and Schwann cells. The
GFAP was also shown in renal glomeruli and peritubular rat
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fibroblasts, Leydig cells, keratinocytes, osteocytes, chondrocytes of the epiglottis and bronchi, and cells of the pancreas and
liver. These cells were described for the first time in 1971 [54]
and in 1991 in humans, mapping on chromosome 17q21 [55]. It
is closely related to vimentin, desmin, and periferina, which are
involved in cytoskeletal structures. The GFAP is involved in
many cellular processes, such as maintenance of cell structure
and movement, cellular communication and blood-brain barrier
and also plays an active role in mitosis [56]. In adult cells, many
functions of the protein have been discovered using knockout
mice for GFAP. These mice lack the intermediate filaments in
the hippocampus and white matter spinal cord. Research shows
that in older mice there is a degeneration of astrocytes,
myelination becomes abnormal, white matter deteriorates, and
there are significant changes in blood-brain barrier. Therefore,
GFAP is involved in maintaining long-term normal myelination
of the CNS [57]. In vitro, using antisense RNA, astrocytes fail
to form extensions usually present. Purkinje cells in the
knockout mice GFAP do not have a normal structure. There are
several diseases associated with an imbalance of GFAP. The
scar Glial is a consequence of several neurodegenerative
diseases and is formed by astrocytes interacting with fibrous
tissue to restore glia around the central tissue [58]. The upregulation of GFAP may be implicated. GFAP and S-100B
protein were examined in the CSF of MS patients [59]. The
CSF levels of GFAP and S100B were elevated in patients with
relapses and disease progression. Both proteins can serve as
markers of glial proliferation in demyelination areas and axonal
damage [60]. As S100B protein is also expressed by oligodendrocytes, it is possible that its levels in CSF may reflect not
only astrogliosis, but remyelination. However, its usefulness in
the diagnosis and prognosis of the disease has not been
established.
Neurofilament proteins are possible markers of disease
progresión. Neurofilaments proteins are three subunits, codify
by different genes, known as the high molecular weight NF
subunit (NFH, 180 to 200 kDa), the medium molecular weight
NF subunit (NFM, by 130 to 170 kDa) and low molecular
weight NF subunit (NFL, 60 kDa) [61,62]. The Triplets of NF
proteins are intermediate filaments of type IV expressed only in
neurons and have a characteristic domain structure. The NFM
subunits have a large number of phosphorylation sites. The
most of these sites are phosphorylated [61] in the axon.
Phosphorylated forms of neurofilament proteins are related to
the integrity of the axon. The changes alter the surface charge
density of NF and NF move away neighbors who have similar
charge. For this reason, observe the various gauges of
intermediate filaments in relation to the degree of ionization of
molecules and the attractive and repulsive forces between them
[63]. Axonal injury induce nonphosphorylated neurofilaments
wich can not maintain normal function. Antibodies against
nonphosphorylated neurofilaments have been useful in the
detection of axon damage. Recently, determination of these
antibodies in CSF has been used to detect the degree of axonal
injury [64]. The study found that high levels of neurofilament
protein in CSF predicts the ME developed. Neurofilament light
chain is the principal protein increased in most patients relapse
[59,65,66]. However, there is some evidence that neurofilament
heavy chain level in CSF may be elevated in patients with optic
neuritis. These proteins can predict the improvement of the
lesions [60]. On the other hand, antibodies against neurofilaments in the CSF of patients with MS are related to relapse
and disease progression and may serve as markers of
progressive axonal damage. However, we do not know if these
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[7]
antibodies have a role in the pathogenesis of relapsing and
progressive forms of multiple sclerosis.
Different proteins associated with inflammation have been
analysed In MS (lymphokines, prostaglandins, chemokines, and
C5b-9) as markers of the disease [44,67,68]. IL1, IL12, IL10,
TGF-β, TNF-α, INF and MMP-9 are also altered in disease
progression [69-72]. Although some authors found a correlation
between MS and these CSF markers [73-76] none of them can
be used to determine the clinical outcome. Some myelin
proteins have been identified in the CSF as markers of
demyelination. MBP-like material” (MBPL) can be detected in
the CSF during acute exacerbations in 80% patients with MS
[77-80]. However, the levels of this protein may be abnormal in
other neurological disorders, and their presence is only a marker
of myelin damage. It has been suggested that detection of
certain MBP fragments may be more specific for MS
exacerbations. Thus, in patients with cerebrovascular events the
fragments of MBP in CSF is significantly different from the
fragments observed in MS patients [81]. The usefulness of these
specific fragments has not yet been demonstrated. Today MBP
in CSF of MS can be used to confirm a clinical exacerbation.
This protein has high levels for 4-6 weeks. However, normal
values of MBP do not imply inactivity disease. Moreover, at
this moment, there are no markers for the detection of
remyelination in the CSF.
At present there is no biomarker that meets the requirements
to be considered a surrogate marker for clinical endpoints in
multiple sclerosis. Because of its fluctuating nature biomarkers
of immune activation are not suitable for this purpose. It is
important to identify candidates who reflect pathophysiological
mechanisms in this disease. These new biomarkers are likely to
arise from the use of recent techniques for analyzing the gene
expression profiling, proteomics, metabolic and biochemical. It
is necessary to standardize the collection and measurement
methods to allow comparison across multiple studies. It is
crucial to the realization of large multicenter clinical trials to
allow assessment of biomarkers in multiple sclerosis, because
its valuation is essential for progress in clinical research of this
disease. In this context, the inability to find bone marrow
biopsies or brain damaged makes it very difficult to identify
molecular markers. The CRF is the only body part that could be
monitored to information on the health of the CNS to the point
of sometimes referred to as "liquid biopsy".
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
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