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Demyelinating diseases
(Multiple scleorsis)
Dr mohamed rizk khodair
Lecturer of neurology
October 6 university
Classification of myelin disorders
Dysmyelinating disorders (leukodystrophy)
Abnormal myelin synthesis
1- adrenoleukodystrophy
2-metachromatic leukodystrophy
3- canavan disease
4-alexander disease
5-krabe disease
Demyelinating disorders
Damage to previous normal myelin
1-autoimmune : MS, Transverse myelitis ,
NMO
2- infections : HIV
3-toxic & metabolic : B12 deficiency ,
carbon monoxide
4- vasculitis
Multiple sclerosis
"It is an immune-mediated inflammatory
demyelinating disease of the central nervous
system characterized by remissions and relapses
and causing chronic disability."
• Disseminated in time and place, The
hallmark of MS is symptomatic episodes
that occur months or years apart and
affect different anatomic locations. See
the image below.
• Characterized by relapses and remissions or
a progressive course.
MRI of the head of a 35-year-old
man with relapsing-remitting
multiple sclerosis. MRI reveals
multiple lesions with high T2
signal intensity and one large
white matter lesion. These
demyelinating lesions may
sometimes mimic brain tumors
because of the associated edema
and inflammation.
Common sites of demyelination:
• Optic nerve
• Around lateral ventricles,
• Corpus callosum,
• Cortical-subcortical junction,
• Brainstem,
• Cerebellum
• Cervical cord.
Etiology and risk factors:
1-genetic factors:
A. Sex: Women are more likely to have MS than men by a 2:1 ratio.
B. Racial Group: Whites are more than twice as likely as other races to develop MS
C. Family History: First-degree relatives are generally greater risk of developing MS than the general
population.
D. Genetic factors : Association with certain HLA types e.g. HLA-DR2
2- environmental factors:
• Latitude: above and below 40° latitude, MS is more common.
• Socioeconomic : It is least common in the lower class and in rural residence.
• Infection: Viral infections may include shingles, chicken pox, measles, or certain herpes
• Factors with the strongest evidence for involvement in MS are Epstein-Barr virus (EBV}, infectious
mononucleosis, smoking, and latitude/vitamin D.
Pathogenesis
• Macrophages engulf unknown antigen --
> represent it surface of macrophages on
HLA Dr2 and become APC
• APC is adhesion with T lymphocytes.
(CD4 cells) by T cell receptors and HLA
dr2
Signal 1 stimulation
• APC release B7 protein and CD4 release
CD28
Signal 2 stimulation
APCs engulf the
unknown antigen
It expresses a piece of that antigen on its
membrane surface on MHC 2 complex.
Another name for MHC 2 complex is HLA DR2
(S
igna l 1 s
timula tion)
Antigen
MHC 2 complex
APCs presents
the antigen to a
T- helper cell
T- helper cell has a receptor
that can recognize that antigen
anywhere else in the body.
CD4+ molecules connect the
APCs to T- helper cells
CD4+
When this
connection
occurs
T- helper cells release
cytokines and start
proliferating.
(S
igna l 2 s
timula tion)
The T- helper cells have a very particular
TCR that recognizes that specific antigen
Strangely this antigen may resemble
or have a very similar configuration to
a protein that is present within Myelin
Myelin Basic Protein
Antigen ͌
So, T cell Receptors are now
recognizing that antigen and
also other proteins within our
bodies that maybe mimic that
antigen. It is called Molecular
Mimicry.
IL-2
IL-12
IL-27
IFN-ϒ
APC
APC (HLA DR2 ) release cytokines
IL 12 & gamma interferon T
helper 1 (cell mediated) release
gamma interferon, TNF B stimulate
macrophage to release TNF alpha
APC ( HLA DR2 ) release
cytokines IL4, IL10 T
helper 2 (cell humoral)
stimulation B cells. release
autoantibodies
T cells (CD4 cells)
T cells release IL2
autoactivation of CD25
more activation
T cells S1P1 receptor & alpha 4
integrin lymph node S1P1
receptor enter T cells inside lymph
node internalization for more
proliferation exist from LN
CNS is a Target
• To enter BBB  alpha 4 integrin adhesion
with VCAM 1  upregulation of MMP 
open BBB  T cells enters CNS
• T cells adhesion with microglia
• Signal 1 and 2. repeated inside CNS
• TNF alpha 
• Auto antibodies  complement fixation 
destructed myelin , oligodendrocytes and
open BBB again
clinical pattern of MS:
1. Relapsing- remitting MS (RRMS, 85%):
• Attacks with complete/ incomplete recovery.
• Stable course (no progression) between attacks.
2. Secondary progressive MS (SPMS):
• Initially relapsing-remitting, then progression± attacks
3. Primary progressive MS (PPMS):
• Gradual decline • No attacks.
4. Progressive relapsing MS (PRMS):
• Initial gradual deterioration.
• Subsequent episodes.
Relapses are defined as new or worsening neurologic
symptoms that occur in the absence of fever or
infection, last over 24 hours, and are preceded by 30
days of relative neurologic stability.
Recent MS phenotypes
1) RRMS: active or not active
2) Progressive disease (PPMS or SPMS):
a) Active and with progression.
b} Active and without progression.
c) Not active and with progression.
d) Not active and without progression (stable
disease}.
Clinical Manifestations of MS
Attacks lasting> 24 hours, spaced at least 1 month apart
1} Cognitive and Affective Symptom:
• Abnormalities of working memory, attention, speed of information processing, and executive function.
• Affective disorders: Depression ,Hypomania or mania.
2} Cranial Nerve Manifestations: (brain stem affection)
Visual Manifestations: very common, usually unilateral, or bilateral.
A) optic or retro bulbar neuritis :
• unilateral or bilateral.
• Acute to subacute loss of visual acuity.
• Pain in or behind the eye, increase with eye movement.
• Tender eyeball on pressure.
• Color vision deficits & field defect due to lesion in optic nerve, chiasma, or tract.
B)Ocular Nerves:
• 6th nerve palsy, 3rd or isolated 4th palsies
(infrequent}.
• Internuclear ophthalmoplegia
(pathognomonic) ( lag of adducting eye,
& nystagmus of abducting eye during
horizontal ocular movements} due to
medial longitudinal bundle (MLB} lesion
diplopia without squint.
• Horizontal and vertical gaze palsies
• One and half syndrome (horizontal gaze
palsy to one side + impaired adduction to
other}.
• Nystagmus
C)Trigeminal neuralgia: Unilateral or bilateral.
• Plaque in pons affecting; nuclei or nerve.
• Brisk jaw is common.
D) Auditory and vestibular manifestations; vertigo .
E) Dysphagia and dysarthria: due to pseudo bulbar palsy.
F) VII nerve palsy : hemifacial spasm
3) Motor Manifestations:
1. Fatigability .
2. UMNL:
• Weakness, commonest paraparesis "may be monoparesis, hemiparesis, quadriparesis."
• Marked spasticity most disabling ~ painful spasms ..
• Deep reflexes are markedly increased with clonus.
• lost abdominal reflexes as early sign.
• Extensor planter response.
3. Incoordination: cerebellar affection~ Ataxia (common); manifestations as intention tremors, ataxia
gait, titubation; truncal ataxia, dysarthria, nystagmus.
4) Sensory Manifestations:
a) Deep sensation due to posterior column affection especially cervical segment.
1. Paresthesia, tingling and numbness.
2. Sense of swelling or tight bandage in the limb and trunk. ·'
3. Impaired vibration deep sensation sense of position.
4. lhermitte's symptom and sign; electric like pain in the back and shoulder on bending the neck.
b) Superficial sensation: paresthesia and numbness; level "ascending," Brown
Squared syndrome.
c) Cortical sensations: impaired.
5) Autonomic Involvement:
A) bladder: due to UMNL: urgency, hesitancy, precipitancy, increase residual volume, nocturia, and
recurrent urinary tract infection.
B) Sexual dysfunction: impotence, fatigue, loss of libido, or may be psychogenic.
C) Constipation or fecal incontinence.
6) Myelopathy :
A) Acute transverse myelitis : paraparesis , sensory level , autonomic manifestation
B) Chronic progressive myelitis in progressive pattern
Uhthoff's phenomenon
Uhthoff's phenomenon (also known as Uhthoff sign or Uhthoff syndrome) is described as temporary,
short-lived (less than 24 hours), and stereotyped worsening of neurological function among multiple
sclerosis patients in response to increases in core body temperature.
It causes a decrease in the speed of action potentials in the central nervous
system (CNS). Heat may increase the time when voltage-gated sodium channels
are inactivated, which delays further action potentials. This is worsened by the
demyelination caused by MS.
Diagnosis of multiple sclerosis in adults :
1-MRI: has improved the diagnostic accuracy of multiple sclerosis
A. Acute lesion : observed as Gadolinium enhancement, appears as a very early sign of the formation of a new lesion
and is perhaps a marker of inflammation.
Site of patches :
Periventricular white matter,
• deep white matter
• centrum semiovale
• corpus callosum (Dawson fingers).
• posterior optic radiation.
• juxtacortical .
• Brain stem , cerebellar & midbrain .
• Cervical spinal segment.
B. Chronic lesions : hyperintensity also without Gadolinium enhancement
C. MS Plaque as a hyperintense area in T2 weighted images. The relationship between the number of T2-weighted
lesions and the degree of clinical disability is poor.
Dawson finger
2-Evoked potentials:
Detect whether there is any problem of slowing or
blockade of conduction in the auditory, visual, or
somatosensory, motor pathways.
Visual Evoked potentials :Delays in latencies indicate
demyelination in the anterior visual pathways.
• They are abnormal in 80- 90% with definite MS.
• They Can reveal clinically silent MS lesions in the visual
pathway.
3-CSF examination:
Increased levels of oligoclonal bands of IgG in
75-90% & IgG index of patients
Three Categories of Treatment
 Treatment of Exacerbations
 Disease modifying drugs
 Specific MS symptom treatment
Treatment of relapse: ( during attack )
Treatment of exacerbations must be done with glucocorticoids to Reduce swelling and inflammation
in the plaques of demyelination, accelerate recovery.
- Intravenous methylprednisolone (pulse therapy) 0.5-1gm/day for five days, followed by a short
course of oral prednisone.
Complications of corticosteroid :
a) Fluid retention and hypokalemia.
b) Gastric ulcer and hemorrhage.
c) Psychosis, anxiety and insomnia.
d) Infections.
e) Osteoporosis and avascular necrosis of the head of femur.
Disease modifying agents (between attack )
beta interferon , fingolimod , natalizumab , ocrelizumab & azathioprine
Thank you
mohamedrizk.med@o6u.edu.eg

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demyelinated disorder: multiple sclerosis.pptx

  • 1. Demyelinating diseases (Multiple scleorsis) Dr mohamed rizk khodair Lecturer of neurology October 6 university
  • 2. Classification of myelin disorders Dysmyelinating disorders (leukodystrophy) Abnormal myelin synthesis 1- adrenoleukodystrophy 2-metachromatic leukodystrophy 3- canavan disease 4-alexander disease 5-krabe disease Demyelinating disorders Damage to previous normal myelin 1-autoimmune : MS, Transverse myelitis , NMO 2- infections : HIV 3-toxic & metabolic : B12 deficiency , carbon monoxide 4- vasculitis
  • 3. Multiple sclerosis "It is an immune-mediated inflammatory demyelinating disease of the central nervous system characterized by remissions and relapses and causing chronic disability." • Disseminated in time and place, The hallmark of MS is symptomatic episodes that occur months or years apart and affect different anatomic locations. See the image below. • Characterized by relapses and remissions or a progressive course.
  • 4. MRI of the head of a 35-year-old man with relapsing-remitting multiple sclerosis. MRI reveals multiple lesions with high T2 signal intensity and one large white matter lesion. These demyelinating lesions may sometimes mimic brain tumors because of the associated edema and inflammation.
  • 5. Common sites of demyelination: • Optic nerve • Around lateral ventricles, • Corpus callosum, • Cortical-subcortical junction, • Brainstem, • Cerebellum • Cervical cord.
  • 6. Etiology and risk factors: 1-genetic factors: A. Sex: Women are more likely to have MS than men by a 2:1 ratio. B. Racial Group: Whites are more than twice as likely as other races to develop MS C. Family History: First-degree relatives are generally greater risk of developing MS than the general population. D. Genetic factors : Association with certain HLA types e.g. HLA-DR2 2- environmental factors: • Latitude: above and below 40° latitude, MS is more common. • Socioeconomic : It is least common in the lower class and in rural residence. • Infection: Viral infections may include shingles, chicken pox, measles, or certain herpes • Factors with the strongest evidence for involvement in MS are Epstein-Barr virus (EBV}, infectious mononucleosis, smoking, and latitude/vitamin D.
  • 7. Pathogenesis • Macrophages engulf unknown antigen -- > represent it surface of macrophages on HLA Dr2 and become APC • APC is adhesion with T lymphocytes. (CD4 cells) by T cell receptors and HLA dr2 Signal 1 stimulation • APC release B7 protein and CD4 release CD28 Signal 2 stimulation
  • 8. APCs engulf the unknown antigen It expresses a piece of that antigen on its membrane surface on MHC 2 complex. Another name for MHC 2 complex is HLA DR2 (S igna l 1 s timula tion) Antigen MHC 2 complex APCs presents the antigen to a T- helper cell T- helper cell has a receptor that can recognize that antigen anywhere else in the body. CD4+ molecules connect the APCs to T- helper cells CD4+ When this connection occurs T- helper cells release cytokines and start proliferating. (S igna l 2 s timula tion) The T- helper cells have a very particular TCR that recognizes that specific antigen Strangely this antigen may resemble or have a very similar configuration to a protein that is present within Myelin Myelin Basic Protein Antigen ͌ So, T cell Receptors are now recognizing that antigen and also other proteins within our bodies that maybe mimic that antigen. It is called Molecular Mimicry. IL-2 IL-12 IL-27 IFN-ϒ
  • 9. APC APC (HLA DR2 ) release cytokines IL 12 & gamma interferon T helper 1 (cell mediated) release gamma interferon, TNF B stimulate macrophage to release TNF alpha APC ( HLA DR2 ) release cytokines IL4, IL10 T helper 2 (cell humoral) stimulation B cells. release autoantibodies T cells (CD4 cells) T cells release IL2 autoactivation of CD25 more activation T cells S1P1 receptor & alpha 4 integrin lymph node S1P1 receptor enter T cells inside lymph node internalization for more proliferation exist from LN
  • 10.
  • 11. CNS is a Target • To enter BBB  alpha 4 integrin adhesion with VCAM 1  upregulation of MMP  open BBB  T cells enters CNS • T cells adhesion with microglia • Signal 1 and 2. repeated inside CNS • TNF alpha  • Auto antibodies  complement fixation  destructed myelin , oligodendrocytes and open BBB again
  • 12. clinical pattern of MS: 1. Relapsing- remitting MS (RRMS, 85%): • Attacks with complete/ incomplete recovery. • Stable course (no progression) between attacks. 2. Secondary progressive MS (SPMS): • Initially relapsing-remitting, then progression± attacks 3. Primary progressive MS (PPMS): • Gradual decline • No attacks. 4. Progressive relapsing MS (PRMS): • Initial gradual deterioration. • Subsequent episodes. Relapses are defined as new or worsening neurologic symptoms that occur in the absence of fever or infection, last over 24 hours, and are preceded by 30 days of relative neurologic stability.
  • 13. Recent MS phenotypes 1) RRMS: active or not active 2) Progressive disease (PPMS or SPMS): a) Active and with progression. b} Active and without progression. c) Not active and with progression. d) Not active and without progression (stable disease}.
  • 14. Clinical Manifestations of MS Attacks lasting> 24 hours, spaced at least 1 month apart 1} Cognitive and Affective Symptom: • Abnormalities of working memory, attention, speed of information processing, and executive function. • Affective disorders: Depression ,Hypomania or mania. 2} Cranial Nerve Manifestations: (brain stem affection) Visual Manifestations: very common, usually unilateral, or bilateral. A) optic or retro bulbar neuritis : • unilateral or bilateral. • Acute to subacute loss of visual acuity. • Pain in or behind the eye, increase with eye movement. • Tender eyeball on pressure. • Color vision deficits & field defect due to lesion in optic nerve, chiasma, or tract.
  • 15. B)Ocular Nerves: • 6th nerve palsy, 3rd or isolated 4th palsies (infrequent}. • Internuclear ophthalmoplegia (pathognomonic) ( lag of adducting eye, & nystagmus of abducting eye during horizontal ocular movements} due to medial longitudinal bundle (MLB} lesion diplopia without squint. • Horizontal and vertical gaze palsies
  • 16. • One and half syndrome (horizontal gaze palsy to one side + impaired adduction to other}. • Nystagmus
  • 17. C)Trigeminal neuralgia: Unilateral or bilateral. • Plaque in pons affecting; nuclei or nerve. • Brisk jaw is common. D) Auditory and vestibular manifestations; vertigo . E) Dysphagia and dysarthria: due to pseudo bulbar palsy. F) VII nerve palsy : hemifacial spasm
  • 18. 3) Motor Manifestations: 1. Fatigability . 2. UMNL: • Weakness, commonest paraparesis "may be monoparesis, hemiparesis, quadriparesis." • Marked spasticity most disabling ~ painful spasms .. • Deep reflexes are markedly increased with clonus. • lost abdominal reflexes as early sign. • Extensor planter response. 3. Incoordination: cerebellar affection~ Ataxia (common); manifestations as intention tremors, ataxia gait, titubation; truncal ataxia, dysarthria, nystagmus.
  • 19. 4) Sensory Manifestations: a) Deep sensation due to posterior column affection especially cervical segment. 1. Paresthesia, tingling and numbness. 2. Sense of swelling or tight bandage in the limb and trunk. ·' 3. Impaired vibration deep sensation sense of position. 4. lhermitte's symptom and sign; electric like pain in the back and shoulder on bending the neck. b) Superficial sensation: paresthesia and numbness; level "ascending," Brown Squared syndrome. c) Cortical sensations: impaired.
  • 20. 5) Autonomic Involvement: A) bladder: due to UMNL: urgency, hesitancy, precipitancy, increase residual volume, nocturia, and recurrent urinary tract infection. B) Sexual dysfunction: impotence, fatigue, loss of libido, or may be psychogenic. C) Constipation or fecal incontinence. 6) Myelopathy : A) Acute transverse myelitis : paraparesis , sensory level , autonomic manifestation B) Chronic progressive myelitis in progressive pattern
  • 21. Uhthoff's phenomenon Uhthoff's phenomenon (also known as Uhthoff sign or Uhthoff syndrome) is described as temporary, short-lived (less than 24 hours), and stereotyped worsening of neurological function among multiple sclerosis patients in response to increases in core body temperature. It causes a decrease in the speed of action potentials in the central nervous system (CNS). Heat may increase the time when voltage-gated sodium channels are inactivated, which delays further action potentials. This is worsened by the demyelination caused by MS.
  • 22. Diagnosis of multiple sclerosis in adults : 1-MRI: has improved the diagnostic accuracy of multiple sclerosis A. Acute lesion : observed as Gadolinium enhancement, appears as a very early sign of the formation of a new lesion and is perhaps a marker of inflammation. Site of patches : Periventricular white matter, • deep white matter • centrum semiovale • corpus callosum (Dawson fingers). • posterior optic radiation. • juxtacortical . • Brain stem , cerebellar & midbrain . • Cervical spinal segment. B. Chronic lesions : hyperintensity also without Gadolinium enhancement C. MS Plaque as a hyperintense area in T2 weighted images. The relationship between the number of T2-weighted lesions and the degree of clinical disability is poor.
  • 23.
  • 25. 2-Evoked potentials: Detect whether there is any problem of slowing or blockade of conduction in the auditory, visual, or somatosensory, motor pathways. Visual Evoked potentials :Delays in latencies indicate demyelination in the anterior visual pathways. • They are abnormal in 80- 90% with definite MS. • They Can reveal clinically silent MS lesions in the visual pathway.
  • 26. 3-CSF examination: Increased levels of oligoclonal bands of IgG in 75-90% & IgG index of patients
  • 27. Three Categories of Treatment  Treatment of Exacerbations  Disease modifying drugs  Specific MS symptom treatment
  • 28. Treatment of relapse: ( during attack ) Treatment of exacerbations must be done with glucocorticoids to Reduce swelling and inflammation in the plaques of demyelination, accelerate recovery. - Intravenous methylprednisolone (pulse therapy) 0.5-1gm/day for five days, followed by a short course of oral prednisone. Complications of corticosteroid : a) Fluid retention and hypokalemia. b) Gastric ulcer and hemorrhage. c) Psychosis, anxiety and insomnia. d) Infections. e) Osteoporosis and avascular necrosis of the head of femur.
  • 29. Disease modifying agents (between attack ) beta interferon , fingolimod , natalizumab , ocrelizumab & azathioprine