MULTIPLE

SCLEROSIS
 Multiple Sclerosis
Also known as MS
A chronic, inflammatory, immune-mediated disease of the central
nervous system (CNS).
The exact cause of MS remains unknown, it is believed to be a
complex interplay of genetic predisposition and environmental
factors.
In MS, the immune system attacks the protective sheath that
covers nerve fibers, known as myelin.
Eventually, the disease can cause permanent damage of the
nerve fibers. Disrupts nerve impulse transmission, resulting in a range
of neurological symptoms.
Signs and Symptoms Tremors and Coordination Problems
Fatigue Muscle Weakness and Spasticity
(Ataxia)
Biochemical Explanation: Biochemical Explanation:
Biochemical Explanation:
• Mitochondrial dysfunction in neurons leads to • Axonal conduction block in motor pathways
decreased ATP production.
• Lesions in the cerebellum and its
due to demyelination.
• Chronic inflammation and immune activation pathways impair motor control.
• Altered ion channel distribution causes
result in energy depletion and increased levels of • Myelin damage interferes with timing
hyperexcitability of motor neurons, leading to
pro-inflammatory cytokines (e.g., TNF-α, IL-1β), and precision of motor signals
spasticity.
which induce fatigue.

Bladder and Bowel Dysfunction

Visual Disturbances (e.g., Optic Neuritis) Numbness or Tingling (Paresthesia)
Manifestation: Urinary urgency,
Biochemical Explanation: Manifestation: “Pins and needles” sensation or
incontinence, or constipation.
• Demyelination of the optic nerve (a common loss of sensation in limbs or face. Biochemical Explanation:
early lesion site) slows or blocks visual signal Biochemical Explanation: • Lesions in the spinal cord disrupt
transmission. • Disruption of sensory pathways in the spinal signals controlling bladder and bowel
• Inflammation causes swelling and impaired cord or brainstem leads to aberrant or delayed function.
function in the optic nerve. signal transmission. • Autonomic nervous system pathways
• Ion channel dysfunction in demyelinated axons are impaired, leading to dysregulation.
contributes to abnormal firing of sensory neurons.
Lhermitte’s Sign
Manifestation: Electric shock-like Cognitive Dysfunction Depression
sensation down the back and limbs • Chronic inflammation reduces
upon neck flexion. Biochemical Explanation: serotonin and dopamine availability.
Biochemical Explanation: • Gray matter atrophy and chronic inflammation impair • Cytokines like IL-6 and TNF-α
• Cervical spinal cord synaptic plasticity. directly influence mood-regulating brain
demyelination causes abnormal • Demyelination in the hippocampus and prefrontal
regions (e.g., the prefrontal cortex
excitation of sensory neurons cortex disrupts neural networks responsible for cognitive
when the neck is flexed function.
Biochemical
Changes in
Multiple
Sclerosis
 Immune System
Dysregulation
T Cell Activation and Infiltration: leads to the attack of
myelin sheaths, contributing to inflammation and
demyelination
B Cell Involvement: produce autoantibodies that
contribute to myelin damage, particularly in relapsing MS
Cytokine Release: Pro-inflammatory cytokines such as
TNF-α, IL-1β, and IL-6 increase BBB permeability, promoting
immune cell infiltration and inflammation in the CNS
 Oxidative Stress
Free Radicals and Reactive Oxygen Species (ROS):
Oxidative stress leads to the generation of ROS that
damage myelin, oligodendrocytes, and neurons
Antioxidant Defense System: Altered levels of
antioxidants like superoxide dismutase and glutathione are
found in MS
Demyelination and
Myelin Breakdown
Lipids and Myelin: Breakdown of myelin, which is lipid-
rich, releases free fatty acids that promote inflammation
and affect myelin integrity
Phospholipase A2 Activation: during demyelination and
releases arachidonic acid, which is metabolized into pro-
inflammatory eicosanoids.
Glutamate Toxicity
Excitotoxicity: Elevated glutamate levels due to reduced
uptake by glial cells cause excitotoxicity, leading to
neuronal cell death.
NMDA Receptor Activation: Increased glutamate
activates NMDA receptors, which elevates intracellular
calcium levels and leads to neuronal apoptosis.
Neurodegeneration
and Axonal Damage
Axonal Loss: Axonal injury in MS contributes significantly
to disability, with biochemical processes like excitotoxicity
and mitochondrial dysfunction being involved.
Neurofilament Biomarkers: Elevated levels of
neurofilament light chain (NFL) in the cerebrospinal fluid
(CSF) correlate with disease activity and progression.
 Blood-Brain
Barrier (BBB)
Disruption
BBB Permeability: Inflammation, oxidative stress, and
immune cell infiltration increase the permeability of the
BBB, allowing further immune attacks on the CNS.
 Diagnostic
Biomarkers
Intrathecal Immunoglobulin G Synthesis
Increased intrathecal immunoglobulin G (IgG) synthesis is a hallmark of
MS, occurring in > 90% of patients with definite MS
IgG synthesis can be identified:
Quantitatively: Elevated IgG index (>0.7), observed in about 70% of
MS patients.
Qualitatively: Presence of IgG oligoclonal bands (OCBs).
 IgG Index
A value of IgG index > 0.7 is an indicator of an increased intrathecal B cell
response and thus indicates the presence of MS.
About 70% of MS patients have an increased IgG index.
Oligoclonal Bands
(OCBs)
OCBs are immunoglobulins produced
within the CNS
seen when patient’s blood serum and CSF
are analyzed in parallel.
created by IgG and IgM produced by
plasma cells in the CNS
The existence of these bands within the
CSF, but not within the serum, is a strong
indicator of intrathecal antibody synthesis
and is found in nearly all patients with
clinically definitive MS.
Oligoclonal Bands
(OCBs)
The presence of CSF-specific IgG
OCBs in patients with MS reflects
proliferation/clonal expansion of
immunoglobulin-secreting B cells and
plasma cells in the central nervous
system (CNS). This indicates an
immune response happening
specifically within the CNS, which is
a hallmark of MS.
 Neurofilament Light Chain (NfL)
A neuron-specific protein released into the
blood and CSF during neuroaxonal injury.
Higher serum (sNfL) or CSF levels
correlate with:
Greater T2 lesion load and more
gadolinium-enhancing T1 lesions in
relapsing-remitting MS (RRMS).
New or enlarging T2 lesions, brain
volume loss, and risk of confirmed
disability worsening over 1–2 years.
 Neurofilament Light Chain (NfL)
a leading serologic biomarker for
evaluating MS disease activity:
sNfL is reduced by effective
treatment
High sNfL values while on disease-
modifying therapy reflect ongoing
neuroaxonal injury and an
insufficient response to
treatment
 Prognostic
Biomarkers
Help improve patient outcomes by providing information about a
patient's likelihood of developing a certain disease or condition and
how they might respond to treatment.

Multiple sclerosis remains a very unpredictable condition.

The type, duration, severity and impact of symptoms will vary from
individual to individual.
 Prognostic Factors for
Multiple Sclerosis (MS):
Demographic factors: Age, gender, and ethnicity
Modifiable factors: Low vitamin D levels, smoking, and obesity
Co-morbidities: Hypertension, diabetes, and psychiatric
disorders
Clinical features: Higher relapse rate, especially early in the
disease course, relapse location in the brain or spinal cord, and
poor relapse recovery
Imaging biomarkers: High T2 lesions, spinal cord or infratentorial
lesions, T1 blackholes, and brain and spinal cord atrophy
Laboratory biomarkers: CSF oligoclonal bands
 Favorable
Prognostic Factors:
Female
<40 years old when diagnosed
Few relapses in the first few years after diagnosis
Complete recovery from relapses
Long intervals between relapses
Symptoms: Sensory in nature (such as numbness
or tingling).
 Poor
Prognostic Factors:
Male, Non-caucasian
Older age at onset
Motor or cerebellar signs at onset / Cognitive impairment
Short interval between first and second attacks
High relapse rate in the early years of the disease
Incomplete remission after first few relapses
Early disability
High lesion load on MRI scan
There is currently no cure for MS, but there are treatments that can help. The
best medicine for you depends on the symptoms and type of MS you have. Talk
to your neurologist about the right combination of treatments for you.
 Treatment
1. Acute Treatment
a. For acute High Dose corticosteroids
exacerbations
First line of treatment
i. Very significant Examples: Methylprednisolone,
visual deficit Prednisone
ii. Extreme weakness Mechanism of action: Anti-inflammatory
iii. Any acute deficit of → glucocorticoids inhibit the release of
the symptoms cytokines and their effects
 Treatment
1. Acute Treatment
a. For acute
exacerbations Plasmapheresis
i. Very significant Second line of treatment
visual deficit If the corticosteroids doesn’t work
ii. Extreme weakness Mechanism of action: Clears out
iii. Any acute deficit of
the antibodies from the plasma
the symptoms
 Treatment
2. Supportive Therapy
a. Spasticity in UMNL (Upper Motor
Neuron Lesion)
-Antispasmodic agents
b. Paresthesia (dorsal column and
spinothalamic tract infection)
Gabapentin
Pregabalin
Tricyclic antidepressant
 Other Regular exercise can
improve a wide range of
treatments symptoms

may include: Physiotherapy for

muscle problems
continence
products
counselling for
depression or
anxiety
 Treatment for relapses
Steroid medicines reduce inflammation in your
01 central nervous system. If you have a relapse of MS,
they can make your symptoms less severe
 Prevention
The main mechanism is by suppression the immune system to
prevent flare ups
1. Immunosuppressors
-Interferon beta
Acts by inhibiting T helper cells from triggering the inflammatory
cascade
-Glatiramer acetate
Inhibits the T cell from releasing cytokines
Acts as a decoy
Glatiramer has proteins that resembles myelin → instead of
interacting with oligodendrocytes, T cells will interact with the drugs
→ acting as a decoy
 References
1. Hafler, D. A., et al. (2005). Multiple sclerosis. The Journal of Clinical Investigation, 115(5), 1122-1131. https://doi.org/10.1172/JCI25412
2. Kiesel, J., et al. (2014). B-cell depletion therapies in multiple sclerosis. Current Opinion in Neurology, 27(3), 289-295. https://doi.org/10.1097/WCO.0000000000000071
3. Steinman, L. (2007). Immunology of relapse and remitting multiple sclerosis. Annual Review of Immunology, 25, 357-397.
https://doi.org/10.1146/annurev.immunol.25.022106.141742
4. Saidha, S., et al. (2012). Elevated reactive oxygen species and mitochondrial dysfunction in multiple sclerosis. Free Radical Biology and Medicine, 52(3), 377-391.
https://doi.org/10.1016/j.freeradbiomed.2011.10.587
5. Mahad, D. H., et al. (2008). Mitochondrial changes in multiple sclerosis. The Journal of Neuroscience, 28(14), 3629-3637. https://doi.org/10.1523/JNEUROSCI.5359-07.2008
6. Ghorbani, S., et al. (2015). Oxidative stress and antioxidant defense in multiple sclerosis. Journal of Clinical Neuroscience, 22(5), 833-839.
https://doi.org/10.1016/j.jocn.2014.10.022
7. Selmaj, K. W., et al. (2011). Myelin breakdown and lipids in multiple sclerosis. Neurochemical Research, 36(9), 1641-1649. https://doi.org/10.1007/s11064-011-0434-0
8. Yong, V. W., et al. (1991). Phospholipase A2 activation in demyelination in multiple sclerosis. Nature, 354(6353), 349-352. https://doi.org/10.1038/354349a0
9. Zhao, Y., et al. (2009). Glutamate excitotoxicity in multiple sclerosis: A possible therapeutic target. Neuroscience Letters, 466(3), 169-172.
https://doi.org/10.1016/j.neulet.2009.09.001
10. Trapp, B. D., et al. (1998). Axonal transection in the lesions of multiple sclerosis. The New England Journal of Medicine, 338(5), 278-285.
https://doi.org/10.1056/NEJM199801293380502
11. Kuhle, J., et al. (2016). Neurofilament light chain as a biomarker for neuronal damage in multiple sclerosis: A review. Multiple Sclerosis Journal, 22(13), 1591-1600.
https://doi.org/10.1177/1352458516640292
12. Ziv, Y., et al. (2009). The blood-brain barrier in multiple sclerosis: Pathology and clinical implications. The Lancet Neurology, 8(5), 420-432. https://doi.org/10.1016/S1474-
4422(09)70069-0
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