Multiple Sclerosis Flashcards
Myelination
in the CNS and PNS
Myelin is the spiral extension of a glial plasma membrane
that is visualized by electron-dense major dense lines (MDL)
and intraperiod lines (IPL) at the compacted intracellular and
extracellular membrane surfaces, respectively.
Oligodendrocytes myelinate central nervous system (CNS)
axons and Schwann cells myelinate peripheral nervous
system (PNS).
Schmidt-Lanterman incisures (SLI) provide cytosolic channels
through compact PNS myelin.
Radial components are adhesive tight junction strands
specific to CNS myelin.
Myelination
Plasticity and Molecular control
A common belief: once developmentally synthesized, myelin is exceptionally
static. It is not. Myelination is a plastic process.
OPCs continue to proliferate and differentiate, and myelin is slowly but
continuously remodeled in healthy adults. Importantly, myelination in the human
brain can be triggered by functional activity, including reading, practicing the
piano, and juggling. On the other hand, social isolation negatively impacts
myelination. Thus, myelination is not only a prerequisite for but also a
consequence of normal activity.
Molecular control: Several metabolic interactions between oligodendrocytes and
myelinated axons in the central nervous system (axoglial symbiosis). (a) Glucose is
taken up from the bloodstream by endothelial cells and transferred to astrocytes via glucose
transporters (GLUT1). (b) In astrocytes, glucose undergoes glycolysis or may be stored in the
form of glycogen. (c,d) Astrocytic metabolites can be transmitted to neurons and
oligodendrocytes via specific transporters and gap junctions. (e,f) Monocarboxylate
transporters (MCT) allow the oligodendrocyte-to-axon transfer of pyruvate/lactate to gain
ATP via the mitochondrial tricarboxylic acid (TCA) cycle. (g) In neurons, the transporter
Aralar transfers aspartate from mitochondria into the cytosol for its NAT8L (N-
acetyltransferase 8-like)-dependent conversion into N-acetylaspartate (NAA). The
oligodendroglial enzyme aspartoacylase (ASPA) hydrolyses NAA. The resulting acetate may
be used for the synthesis of myelin lipids. (h,i) Axoglial interactions also involve signaling by
neurotrophic factors and the transfer of molecules via multivesicular bodies (MVB)
Multiple Sclerosis
A demyelination disease
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating and
neurodegenerative disease of the central nervous system (CNS).
The pathological hallmark of MS is the accumulation of demyelinating
lesions that occur in the white matter and the grey matter of the brain
and spinal cord.
The clinical presentation of MS is heterogeneous and depends on the
location of demyelinating lesions within the CNS. Although no clinical
findings are unique to MS, some are highly characteristic of the
disease.
Typically, the onset of MS is characterized by an initial clinical attack
(defined as CIS) in ~85% of patients, which consists of an unpredictable
episode of neurological dysfunction owing to demyelinating lesions in
the optic nerve (causing optic neuritis, which in turn causes
dyschromatopsia & eye pain), spinal cord (causing myelitis), brainstem
or cerebellum (leading to brainstem and/or cerebellar syndromes) or
the cerebral hemispheres (cerebral hemispheric syndrome).
Similar to the CNS in MS, peripheral nerves are affected by
neuroinflammation and demyelination-dependent pain, morbidity, and
mortality in Guillain-Barré syndrome and chronic inflammatory
demyelinating polyneuropathy.
Ref: 10.1038/s41572-018-0041-4
Radiological examples of MS demyelinating events. Focal lesions (arrows) in:
a. the right optic nerve in a patient with acute optic neuritis
b. the left pons and the right middle cerebellar peduncle in a patient with diplopia
c. the cerebellar hemispheres in a patient with vertigo
d. the cervical spinal cord in a patient with paresthesia and Lhermitte sign
e. the left cerebral hemisphere in a patient with right sensorimotor hemisyndrome
Multiple Sclerosis
Clinical course
The clinical course of MS are heterogeneous.
The National MS Society Advisory Committee defined four clinical
courses of MS:
1. relapsing–remitting MS (RRMS),
2. secondary progressive MS (SPMS),
3. primary progressive MS (PPMS), and
4. progressive relapsing MS (PRMS).
RRMS accounts for ~85% of patients and is characterized by the
occurrence of relapses at irregular intervals with complete or
incomplete neurological recovery. Average relapse frequency is ~1.1
per year early in the disease course but decreases with advancing
disease, increasing neurological dysfunction, and age.
Most patients with RRMS will develop SPMS, which is characterized
by progressive, irreversible disability that occurs independently of the
presence of relapses.
10–15% of patients present with PPMS, which is characterized by
disease progression from the onset, resulting in gradual, progressive
and permanent neurological deficits for >1 year without relapses.
PRMS is rare and is characterized by progressive disease from the
onset and with acute relapses.
Multiple Sclerosis
Diagnosis criteria and a case study
A female patient, now 50-year-old, presented with a 29-year history of neurologic
difficulties. She had reported having diplopia at age 21 years, making a good
recovery. She was diagnosed with RRMS just 2 years later, after an episode of
subacute right-sided weakness and cerebrospinal fluid (CSF) analysis demonstrating
oligoclonal bands (OCBs). She was treated with adrenocorticotropin hormone
(ACTH). Although subsequently she required a right ankle–foot orthosis (AFO), she
was able to return to an active life. Subsequently she developed increasingly severe
relapses every 1 to 2 years, each time undergoing treatment with intravenous (IV)
methylprednisolone. She than began interferon beta-1a intramuscularly in the late
1990s when she visited a new neurologist because of increasing dependence on a
cane and frequent bouts of urinary incontinence. Subsequently, mounting lower
extremity weakness, spasticity, and fatigue evolved but she no longer experienced
distinct flare-ups of her disease. It became increasingly difficult for her to keep up
with the frequent travel that her work as an executive required.
Which of the 4 clinical courses is our patient experiencing?
1. relapsing–remitting MS (RRMS),
2. secondary progressive MS (SPMS),
3. primary progressive MS (PPMS), and
4. progressive relapsing MS (PRMS).
MS
epidemiology
- MS is one of the most widely studied neurological diseases in terms of epidemiology
and it is the primary cause of non-traumatic disability in young adults.. - Approximately 2.3 million people have MS5 worldwide, and this disease is associated
with a high societal economic burden, which was estimated as ~14.6 billion euros in
2010 within Europe and 4.3 billion dollars in the United States in 2013. - MS is mainly found in individuals of European descent and is rare in Asian, black,
Native Americans and Māori individuals. - A higher latitude correlates with increased prevalence and incidence of MS, mainly in
Europe and North America. Low vitamin D levels owing to a lack of sun exposure are
most likely environment risks
Multiple Sclerosis
Causes
MS is a complex disease that is not
caused by a single gene or environmental
factor. Rather, many overlapping causes
contribute to the disease, as shown here.
These may include the action of various
genes and exposure to chemicals,
pathogens, and other external triggers.
The study of epigenetic and other
regulatory mechanisms linked to MS
susceptibility is only beginning to
emerge.
Genome-wide association studies have
identified >200 genetic risk variants for
MS; each variant has a small effect on risk
of disease, and different combinations of
these variants likely contribute to genetic
susceptibility in different patients. Most
of these variants encode molecules
involved in the immune system
Immune pathophysiology
Early Disease
Peripheral immune cells enter the CNS during MS
through the blood vessels of the blood–brain
barrier (BBB), the subarachnoid space (SAS) and
the choroid plexus (dashed arrows).
In MS relapses––prominent in the early phases of
disease––underlying mechanisms involve the
infiltration of cells of the innate and adaptive
immune systems, such as CD4+ and CD8+ T
cells, B cells and myeloid cells, into the CNS
parenchyma with perivascular distribution around
post-capillary venules of the BBB.
These immune cells, together with resident
activated microglia and astrocytes, contribute to
oligodendrocyte injury, demyelination and neuro-
axonal injury through cell contact- dependent
mechanisms and the secretion of soluble factors.
Immune pathophysiology
Late Disease
In later stages, episodic infiltration of immune
cells into the CNS diminishes.
Mechanisms contributing to ongoing tissue injury
(and the clinical manifestations of progressive
disease) include 1) loss of neuro-axonal symbiosis
due to oligodendrocyte death or damage owing
to acute or chronic oxidative stress promoted by
innate and adaptive immune cell activation, 2)
mitochondrial dysfunction, 3) loss of myelin
trophic support, 4) hypoxia (energy deficiency),
altered glutamate homeostasis and a chronic pro-
inflammatory environment.
Chronic inflammation is mediated by ongoing
CNS-compartmentalized inflammation involving
meningeal immune cell infiltrates (for example, B
cells) that can form lymphoid-like structures and
by CNS- resident innate cells (for e.g.,, microglia
Epstein–Barr
virus (EBV)
infection
and MS
Among individuals who are EBV positive, those with a history of infectious mononucleosis or with high antibody titres against EBV
nuclear antigens have an increased risk of developing MS.
Figure above demonstrates possible mechanisms: a, During primary EBV infection, especially infectious mononucleosis, autoimmune T
cell and B cell responses could be primed (1). The population of primed cells could then expand as a result of cross-recognition of
myelin and other autoantigens (2). T cell priming might be performed directly by EBV-infected B cells (3) or through presentation of
released viral antigens by dendritic cells (4). Migration of these autoimmune B cell and T cell populations to the CNS allows
oligodendrocyte destruction, thereby compromising neuronal function (5). b, In individuals predisposed to MS by their genetic
background, primary EBV infection could also establish a reservoir of EBV-infected B cells that are not efficiently immune controlled (6).
These potent antigen-presenting cells could stimulate autoreactive T cells for myelin recognition or virus-specific T cells that then
promote inflammation in the CNS (7).
Vaccines that might prevent EBV infection are currently being developed. If effective, these vaccines would be expected to prevent most
MS cases. Targeting EBV with therapeutic vaccines or antiviral drugs could represent a novel treatment strategy for MS
