DISEASE OF CNS(MS) AND NERVE

AND MUSCLE DISORDER(MG)

Presented by: Rabina Ramtel

MSc.Clinical Biochemistry
2nd year
 Outline
 Myasthenia gravis
 Introduction
 Epidemiology and etiology
 Pathophysiology
 Clinical manifestations
 Diagnosis
Multiple sclerosis
 Introduction
 Epidemiology and etiology
 Pathophysiology
 Clinical manifestations
 Diagnosis
Introduction

 Myasthenia gravis (MG) is a

neuromuscular junction (NMJ)
disorder

 The hallmark of myasthenia gravis

is muscle weakness that increases
during periods of activity and
improves after periods of rest.

 The underlying defect is a decrease

in the number of available
acetylcholine receptors (AChRs) at
NMJs due to an antibody-mediated
autoimmune attack.
Epidemiology and etiology

 MG has a prevalence as high as 200 in 100,000.

 MG can occur at any age and it has a bimodal peak in incidence:
 2nd-3rd decade of life: predominantly females
 6th-7th decade of life: predominantly males

Approximately 80-90% of cases of MG are due to the formation of AChR-

antibodies.
 Thymus gland
 Myoid cells
 Other factors
Several genetic factors have been implicated in the development of MG
including human leucocyte antigens (HLA) HLA-B8, DRw3, and DQw2,
which are involved in antigen presentation. 
 The Thymus in Myasthenia Gravis
 Central organ for immunological self tolerance and contains all the
necessary elements for the pathogenesis of myasthenia gravis; myoid
cells, APC and immunocompetent T-cells.

 Thymic abnormalities cause the breakdown in tolerance that causes an

immune-mediated attack on AChR

 Myoid cells in the thymus resemble skeletal muscle cells and are central
to the development of autoimmunity to Ach-R

 10 - 15% of patients with MG have a thymoma and 85% have

hyperplastic changes that indicate an active immune response. MG
Patients with thymoma usually have more severe disease, higher levels
of AChR antibodies, and more severe EMG abnormalities than patients
without thymoma.
Fig: Illustrations of a normal presynaptic neuromuscular junction
Harrison’s principle of internal medicine
Fig: a normal postsynapatic terminal
Harrison’s principle of intennal medicine
 Pathophysiology

FIG : Speculative mechanisms of AChR MG immunopathology Front. Immunol., 27 May 2020 | 

https://doi.org/10.3389/fimmu.2020.00776
Fig: a myasthenic neuromuscular junction.
Harrison’s principle of intennal medicine
 Pathophysiology
 In MG, the fundamental defect is a decrease in the number of
available AChRs at the postsynaptic muscle membrane.
 In addition, the postsynaptic folds are flattened, or “simplified.”
 These changes result in decreased efficiency of neuromuscular
transmission. Therefore, although ACh is released normally, it
produces small end-plate potentials that may fail to trigger
muscle action potentials. Failure of transmission results in
weakness of muscle contraction.
 In the myasthenic patient, the decreased efficiency of neuromuscular
transmission combined with the normal rundown results in the
activation of fewer and fewer muscle fibers by successive nerve
impulses and hence increasing weakness, or myasthenic fatigue.
 This mechanism also accounts for the decremental response to
repetitive nerve stimulation seen on electrodiagnostic testing.
 MG is an autoimmune disorder most commonly caused by antiAChR
antibodies. The anti-AChR antibodies reduce the number of available
AChRs at NMJs by three distinct mechanisms:

 accelerated turnover of AChRs by a mechanism involving cross-

linking and rapid endocytosis of the receptors;
 damage to the postsynaptic muscle membrane by the antibody in
collaboration with complement;
 blockade of the active site of the AChR (i.e., the site that normally
binds Ach).
MuSK - MG immunopathology

FIG: Speculative mechanisms of MuSK MG immunopathology

Front. Immunol., 27 May 2020 | 
https://doi.org/10.3389/fimmu.2020.00776
 MuSK - MG immunopathology

FIGURE: Schematic of IgG4 Fab-arm

exchange in MuSK MG.

• Rather than inducing destructive damage to the NMJ or antigenic modulation, the anti-
MuSK Abs mask the binding sites on MuSK that interact with its binding proteins
(ligands), including lrp4/agrin and ColQ, thereby blocking MuSK function

• Blockade of MuSK ligand binding leads to a reduced postsynaptic density of

AChRs and impairs their alignment in the postsynaptic membrane
 Clinical manifestation

Note : In Musk –MG severe involvement of neck, shoulder, facial and bulbar-innervated
muscles, although there is considerable variability from patient to patient. When
extremities are involved proximal muscles are more affected than distal ones
 Classification and subtypes

Clinical subtypes Thymic abnormalities

 Ocular MG: weakness limited to eyelids • Normal
extraocular muscles. Only 50% • Thymoma: 10-15% of
seropositive.  patients with MG
 Generalised MG: can affect numerous • Hyperplasia
muscle groups including neck, bulbar, • Atrophy
limbs, respiratory and ocular. Up to
90% seropositive.

Antibody subtypes Age of onset

 MG with AChR-Ab: 80-90% of cases
Neonatal
Juvenile
 MG with Anti-MuSK: ~4% of cases
Early-onset (< 50 years)
 MG with Anti-LRP4: ~2% of cases Late-onset (≥ 50 years)
 Seronegative myasthenia 
 MYASTHENIC CRISIS

 A rapid and severe deterioration of myasthenia called “myasthenic crisis”

is the exacerbation of the disease process
 usually includes ventilatory failure caused by diaphragmatic and
intercostal muscle weakness.
 can bring patient to the brink of respiratory failure and quadriparesis in
hours
 A intercurrent infection or a sedative medication with NM block may be
the reason
 It can develop at any time after the diagnosis of myasthenia
Harrison’s principle of internal medicine
Bedside tests
 Ice-pack test: 
 Applying ice for two to five minutes to the muscles, reportedly
has a sensitivity and specificity of 76.9% and 98.3%,
respectively, for the identification of MG.

 Acetylcholinesterase is thought to be inhibited at the lower

temperature, and this is the basis for this diagnostic test.

 This generally is performed on the eyelids when a ptosis is

present and is deemed positive if there is a ≥2mm raise in the
eyelid after the ice is removed.
 The edrophonium chloride test (tensilon test)
 Weakness caused by abnormal neuromuscular transmission
characteristically improves after intravenous administration of
edrophonium chloride, commonly referred to as the Tensilon®
Test.

 The edrophonium test uses intravenous administration of

edrophonium chloride to very briefly relieve weakness in people
with myasthenia gravis.

 The drug blocks the degradation (breakdown) of acetylcholine

and temporarily increases the levels of acetylcholine at the
neuromuscular junction.
 Diagnostic testing
 A chest X-ray may identify widening of the mediastinum
suggestive of thymoma.

 Diagnostic imaging of the chest, using computed

tomography (CT) or magnetic resonance imaging (MRI),
may be used to identify the presence of a thymoma.

 MRI of the cranium and orbits may also be performed to

exclude compressive and inflammatory lesions of the
cranial nerves and ocular muscles
Multiple Sclerosis

30th May
 Multiple sclerosis or Disseminated sclerosis

 MS was first described in 1868 by Jean-Martin Charcot.

 The name multiple sclerosis refers to the numerous scars (sclerae

—better known as plaques or lesions) that develop on the white
matter of the brain and spinal cord, due to the presence of lot of
mylein in this region.

 World MS day at 30th May every year

 Multiple sclerosis (MS) is a
demyelinating disease in which the
insulating covers of nerve cells in the
brain and spinal cord are damaged

 Autoimmune disease of the CNS

characterized by chronic inflammation,
demyelination, gliosis (plaques or
scarring), and neuronal loss

 Damage to these sheaths can short

circuit signals traveling along the
nerve fibers, disrupting the normal
flow of communication from the brain
and causing a range of symptoms –
including weakness, sensory
disturbance, fatigue, visual
impairments and loss of coordination.
Prevalence of MS
Epidemiology and Etiology
 Females are affected more than males. The cause of disease is unknown;
may interplay between a viral infection, host immune response and
hereditary alone or in combination .
 Breach in blood brain barrier in genetically predisposing individual would
be responsible for MS.
The BBB has proteins that zip up all intercellular junctions, S1PR2 causes
junctional proteins to unzip,” allowing immune cells to pass in CNS. Once
across the BBB, the immune cells are free to damage the myelin coating of
nerves in the brain and spinal cord.
Immunopathogenesis

Figure 1 | Immune cells involved in the pathology of early MS

Immunopathogenesis

Figure 2 | Immune cells involved in the pathology of late MS

Neurodegeneration processes are the culmination of a cascade of inflammatory
events implemented by infiltrated immune cells,
 Clinical manifestations

Plaques along motor pathways :

Muscles weakness, spasms, tremors,
ataxia, paralysis
Intention
tremor
Dysarthri Nystagm
a us
Difficult or unclear speech Charcots Involuntary rapid eye
Plaques in brain stem that effects neurologic movement
nerve fibers that controls the Plaques in nerves of eye
muscle in the mouth and throat
triad in
Optic nerve : loss of vision i.e
and interfere with conscious and MS optic neuritis
unconscious movements Damage to nerve controlling
eye movements : pain, double
vision.
Uhthoff phenomenon, characterised by a
Lhermitte’s sign: specific sensory
decrease in visual acuity following an increase
symptom, neck flexion causes ‘electric
in body temperature
shocks’ in trunk/limbs
Plaques in sensory pathways
can effect inbound signals like
sensation from skin which
causes symptoms like numbness

Plaques in ANS leads to :1

2
Types of MS

1. Relapsing remitting MS (RRMS)

 Bouts of autoimmune attacks happening
months or even years and causing an increasing
in the level of disability.
 With each attack CNS gets irreversibly
damaged.
 80 -85 % .

2. Secondary progressive MS
(SPMS)
• similar to RRMS but after some time
immune attacks become constant which
cause a steady progression of disability.
• 60 -65%.
3. Primary progressive MS (PPMS)
 Constant attack on myelin which cause a
steady progression of disability over a
person’s lifetime .
 10%.

4. Progressive relapsing MS
(PRMS)
• Constant attack but bouts
superimposed during which the
disability increase even faster.
• 1 -2%.
Diagnosis
Body fluid biomarkers for multiple sclerosis

kFLC- Kappa free light chain NAA- N-acetyl aspartate

CXXL13- CXC motif chemokine 13 Gfap-Glial fibrillary acidic protein
NfL- Neuro filament light chain MOG- antimyelin oligodendrocyte glycoprotein
OCBs in MS are considered products of clonally expanded B cells in the
cerebrospinal fluid (CSF), representing the sum of contributions from B
cells in the brain.Each one of them represent antibody proteins (or protein
fragments) secreted by plasma cells, although why exactly these bands are
present, and which proteins these bands represent, has not yet been fully
Differential diagnosis of MS
Summary
 MG is an antibody-mediated autoimmune disease of the
neuromuscular junction with the cardinal features like weakness and
fatigability of skeletal muscles. The weakness increases during
repeated use (fatigue) or late in the day and may improve following
rest or sleep.
The fundamental defect in MG is a decrease in the number of
available AChRs at the postsynaptic muscle membrane
MULTIPLE SCLEROSIS is a Chronic & progressive Autoimmune
disorder and the most common pattern is the relapsingremitting type
and slightly worsening their over all condition.
Immune cells cause inflammation and damage to oligodendrocytes
in the CNS which leaves behind scarred areas of demyelinated
neurons called plaques which cause variety of symptoms depending
on the location.
 References
 Harrison’s Principle of internal medicine.
 Front.Immunol,04March2020 https://doi.org/10.3389/fimmu.2020.00213
 Diagnosis of Multiple Sclerosis . Joyce Pauline Joseph
 Pathophysiology of multiple sclerosis-180326205010.pdf
 https://downloads.hindawi.com/journals/nri/2019/3741260.pdf
 Front.Immunol.,27May2020https://
doi.org/10.3389/fimmu.2020.00776
 The complex relationship between oligoclonal bands, lymphocytes in
the cerebrospinal fluid, and immunoglobulin G antibodies in multiple
sclerosis: Indication of serum contribution Cheryl Beseler et.al 2017.
 Liis Sabre et.al Circulating miRNAs as Potential Biomarkers in
Myasthenia Gravis: Tools for Personalized Medicine