Neuro ophthalomology of Multiple sclerosis INO one and half syndrome optic neuritis

1. Amr Hassan, M.D.
Associate professor of Neurology
Cairo University
2016
The Neuro-Ophthalmology
of Multiple Sclerosis

2. AGENDA
• Multiple sclerosis (MS): an overview
Aetiology and pathogenesis
Diagnosis
Clinical course
Treatment options
• Opthalmological presentations of MS
2

3. 3

4. 4

5. 5

6. 6

7. MS In EGYPT

8. Genetics
EnvironmentAutoimmunity
Immunopathogenesis of M.S.

9. Autoimmune attack
A healthy neuron with its axon surrounded by myelin
Information flows
A demyelinated neuron
Partial information flow
A degenerated neuron
No information flow
Disability
Neurological
symptoms
9
Immunopathogenesis of M.S.

10. 10
Peripheral activation
Migration of autoreactive T cells
Central reactivation
Myelin damage
Immunopathogenesis of M.S.

11. 11
Immunopathogenesis of M.S.

14. Myelin
14

15. Myelin

16. Immunopathogenesis of M.S.
16
Peripheral activation
Migration of autoreactive T cells
Central reactivation
Myelin damage

17. Immunopathogenesis of M.S.
17
Peripheral activation
Migration of autoreactive T cells
Central reactivation
Myelin damage
Remyelination Axonal loss

18. 18

19. 19
Fingolimod
Fingolimod

20. 20
Clinical course of M.S.

21. Multiple Sclerosis Diagnosis
21
• Diagnosis relies on clinical judgment.
• MS is extremely variable.
• There is no specific test.
• The diagnosis has dramatic implications.

22. Multiple Sclerosis Diagnosis
22
Diagnosis of MS
includes
To prove it is M.S
To exclude other
diagnoses

23. How to diagnose MS?
23
Clinical:
• History and
examination.
• Evidence of CNS
involvement.
• Dissemination in
space and time.
Paraclinical:
• Neuroimaging.
• Evoked potentials.
• CSF analysis.

24. • Dawson criteria: 1916
• Schumacher criteria: 1965
• Poser criteria: 1983
• McDonald criteria: 2001
• McDonald criteria: 2005
• McDonald criteria: 2010
• 2016 -2017 ??
Diagnostic Criteria
All criteria require
dissemination in time and space

25. 1. Dissemination in space: Objective
evidence of neurological deficits
localized to two separate parts of the
CNS
2. Dissemination in Time:
Onset of neurological deficits
separated by at least one month
3. No better explanations!
2010
2014
Diagnostic Criteria

26. • Incorporate use of MRI
• Clinically Isolated Syndrome
+
MRI Dissemination in space
+
MRI Dissemination on time
=
Earlier MS Diagnosis
August
DIS
DIT
November
Diagnostic Criteria 2005
Cerebral
Sp. cord

27. • Incorporate use of MRI
• Clinically Isolated Syndrome
+
MRI Dissemination in space
+
MRI Dissemination on time
=
Earlier MS Diagnosis
August
DIS
DIT
August
Diagnostic Criteria 2010
Cerebral
Sp. cord

28. Magnetic resonance imaging
T1 weighted Pre & Post Contrast
28

29. 29
New Diagnostic Criteria 2010

30. 30
Magnetic resonance imaging

31. Magnetic resonance imaging
T2 weighted images showing plaques
31

32. 32

34. 34

35. D.D. OF M.S. IN MRI
35
1. Age-related changes
2. Acute disseminated encephalomyelitis
3. CNS vasculitis
4. Behçet disease
5. Sjögren syndrome
6. Sarcoidosis
7. Metastatic neoplasm
8. CADASIL (cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy)
9. Binswanger disease
10. Migrainous ischemia

36. D.D. OF M.S. IN MRI
36
11. Cerebrovascular disease
12. Progressive multifocal leukoencephalopathy
13. Inherited white matter diseases
14. Effects of radiation therapy or drugs
15. CNS lymphoma
16. Lyme disease
17. HTLV-1 infection
18. CNS lupus
19. Mitochondrial encephalopathies
20. Antiphospholipid antibody syndrome

37. CSF examination
37
IgG index:
• [IgGCSF/albuminCSF]/[IgGserum/albuminserum]
MS patients elevated IgG index (>1.7). (normal is <0.77)

38. 38
Oligoclonal Bands in CSF

41. 41

42. INVESTIGATIONS

43. Treatment of relapsing remitting multiple
sclerosis (R.R.M.S.)
43
• Treatment of a
relapse
• Disease modifying
therapy (DMT)
• Symptomatic ttt
• Non
pharmacological

44. 44
• Worsening of present symptoms or appearance of new
symptoms
• At least 24 h
Relapse
• 1 month from last attack.
• Not during steroid withdrawal or infection.
• ↑ EDSS ≥ 0.5
Definition of a relapse

45. DMT
45

46. Existing & Emerging MS therapies
Modified from P. Vermersch
Phase I
Phase II
Phase III
Marketed
Interferons
Antiproliferative
agents
Cytolytic mAbs
Symptomatic TxVaccine,
tolerization
Lymphocyte
trafficking
Immune
regulation
Other
Idebenone
BIIB033
Fingolimod
Firategrast
Siponimod
ONO-4641
CS-0777
ELND-002
Tysabri
Daclizumab
Laquinimod
BG12
NI-0801
AZD5904
GRC4039
CCX-140
AIN457
Cladribine
NerispirdineOfatumumab
Belimumab
Ampyra
Ocrelizumab
Sativex
Alemtuzumab
Copaxone
IPX-056
RPI-78M
LY-2127399
Novantrone
Rebif Betaferon
Pixantrone
Peg IFNb
(BIIB017)
ATX-MS-1467
PI2301
RTL1000
Copaxone
generics x2
Azathioprine
Teriflunomide
LV Copaxone
Avonex
= Oral administration
= Injectable
Extavia
Ponesimod

47. BMT
Cyclophosphamide
Mycophenolate mofitil
Mitoxantrone - Fingolimod –
Natalizumab Mitoxantrone
Β Interferons – Glatirmar Acetate
Teriflunomide – Dimethyl fumarate - Leflunomide –
Azathioprine – Methotrexate – Fingolimod*

48. 48

49. AGENDA
• Multiple sclerosis (MS): an overview
Aetiology and pathogenesis
Diagnosis
Clinical course
Treatment options
• Opthalmological presentations of MS
49

50. Role of the Ophthalomolgist!!
50

51. Timing of the therapy key to preventing disability
Time (Years)
Relapsing Remitting Multiple sclerosis Transitional Secondary Progressive MSCISPre-
Clinical
Demyelination
Remission
State of no disease
activity, the period
during which
diminution of
symptoms occurs
due to the
cessation of
inflammatory
processes and
some degree of
reparative
remyelination of
affected axons
Relapses
Acute
Inflammation
Demyelination
First
Clinical
Attack
Axonal loss
Inflammation
Brain
Volume
MRI Activity
Disability
progression
Reflects reactive
astrogliosis, Axonal
Loss and Brain
volume loss.
Starts Reversible
(remyelination) and
ends in permanent
disability
Time window
for early
treatment
Mark S. Freedman: Induction vs. escalation of therapy for relapsing Multiple Sclerosis: the evidence, Neurol Sci (2008) 29:S250–S252

52. 52
More Than a Demyelinating Disease
Time (Years)
DiseaseParameter
INFLAMMATORY ACTIVITYINFLAMMATORY ACTIVITY
NEURODEGENERATIONNEURODEGENERATION
PROGRESSIONPROGRESSION
RelapsesRelapses
cMRIcMRI WMLsWMLs
FLAIRFLAIR T1 Gd+T1 Gd+
FLAIRFLAIR
Rx effectRx effect
Poor Rx effectPoor Rx effect
No NewNo New WMLsWMLs

53. Market Research done by Kantar Health, August, 201453
40%
28%
12%
8%
4%
4%
4%
1st specialty the patient seek
when started feeling
symptoms
Neurologist Ophthalmologist
Orthopedic GP
ENT Cardiologist
IM
32%
68%
Same physician diagnosed the
patients
Yes No
Can we Capture the Multiple Sclerosis
Patients Early in their journey?

54. PRESENTING SYMPTOMS IN MS Total %
SENSORY LOSS IN LIMBS 30.7
VISUAL LOSS 15.9
MOTOR WEAKNESS 14.2
DIPLOPIA 6.8
GAIT DISTURBANCE 4.8
INCOORDINATION 2.9
SENSORY LOSS-FACE 2.8
LHERMITTE’S 1.8
VERTIGO 1.7
BLADDER SYMPTOMS 1
AUTE TRANSVERSE MYELOPATHY 0.7
PAIN 0.5
OTHERS 2.5
POLYSYMPTOMATIC 13.7

55. 55
GOOD RELAPSES BAD
Mild, monofocal 1st relapse Severe , multifocal
Sensory, ON Clinical presentation Motor, cerebellar
Full recovery Response to ttt Residual
Long Time to 2nd relapse Short
Low Relapse rate High
Prediction of prognosis

56. 56
Outcome of MS?

57. How to delay this start? To become this end!
57
The earlier….. the better
Capture the symptoms

58. Neuro-Ophthalmology of Multiple Sclerosis
58
Opthalmological presentations of MS
Vision Ocular motility

59. • Loss of Vision (Monocular and Binocular)
• VF defects
• Diplopia
• Oscillopsia
Neuro-Ophthalmology of Multiple Sclerosis

60. •Monocular
(Central Vision loss)
•Pain
(eye movement)
•Altered colour vision
•Uhthoff’s symptom
•Flashes
Optic Neuritis : Common Symptoms

61. Multiple Sclerosis & Eye problems | 25.08.201661

62. 62

63. 63
An Egyptian Patient

64. • Uhthoff described 3
patients in whom exertion
and fatigue caused a
desaturation in colour
vision
• Patient XVIII had
decreased acuity after
walking around the room
Uhthoff’s Symptom

65. Movement phosphenes in optic neuritis: A new clinical sign
(Davis F, Bergen D, Schauf C, McDonald I, Deutsch W)
Neurology 1976; 26: 1100-1104.
• Bright flashes in dark
• Eye movement
• Differentiate from Lightning Streaks of Moore
• Eye equivalent of L’hermittes symptom
Flashes

66. • Decreased visual acuity
• VF defect
(Central/Altitudinal 29% )
• Dyschromatopsia
• Afferent Pupil Defect
(RAPD)
• Optic disc swelling 35%
• Abnormal Contrast
Sensitivity
• Abnormal VEP
• Altered Flicker
Perception
• Altered depth
perception
• Optic disc pallor
Optic Neuritis: Physical signs

67. Optic Neuritis: Optic Disc

68. 68
Optic Neuritis: VF defect

69. Mental map for diagnosis of ON
69
Optic Neuritis (ON)
ON Typical for MS
MRI Fulfills Criteria
ON Atypical for MS
Red Flags Present
Work Up for
Alternative Diagnoses
Clinical/Imaging Follow Up
Alternative Diagnosis
Established
Further clinical/imaging
typical for MS
MS Diagnosis

70. 70
Optic Neuritis : Red Flags

71. • AION (Ischemic Optic Neuropathy)
• Vasculitic Disorders (i.e. SLE)
• Hereditary (i.e. Leber’s)
• Toxic/Nutritional (ETOH)
• Infectious (i.e.Bartonella, Lyme)
• Inflammatory (i.e. Sarcoid)
• Neoplastic/Paraneoplastic (i.e. lymphoma)
• Compressive (i.e.Tumours, Grave’s orbitopathy)
• Multiple Evanescent White Dot Syndrome [MEWDS]
• Acute Idiopathic Blind Spot Enlargement Syndrome
[AIBSE]).
Optic Neuritis: D.D.

72. • NMO
• CRION
• ADEM
• anti-Myelin oligodendrocyte glycoprotein–
associated (MOG) optic neuritis
Optic Neuritis: D.D.

73. 73
NMO

74. 74
NMO

75. 75
Optic Neuritis: D.D.

76. • Complete blood count (CBC)
• Serum vitamin B-12 and folate levels (eg, bilateral central scotoma)
• Lyme titers (eg, endemic area, tick exposure, rash of erythema chronica
migrans)
• Tuberculin skin testing, chest radiography, or QuantiFERON-TB testing (eg,
tuberculosis [TB] exposure, endemic area)
• Fluorescent treponemal antibody (FTA) testing (eg, syphilis serology) or
nontreponemal testing (eg, Venereal Disease Research Laboratories
[VDRL] testing or rapid plasma reagin [RPR] testing)
• Antinuclear antibody (eg, systemic lupus erythematosus)
• HIV testing (eg, high-risk patients)
• Angiotensin-converting enzyme (ACE) level, chest radiography, lysozyme
(eg, sarcoidosis)
• Erythrocyte sedimentation rate (eg, inflammatory disorders)
• Serum NMO antibody IgG (anti–aquaporin-4 [AQP4] antibody) testing
76
Optic Neuritis: lab workup

77. Mental map for diagnosis of ON
77
Optic Neuritis
ON Typical for MS
MRI Fulfills Criteria
ON Atypical for MS
Red Flags Present
Work Up for
Alternative Diagnoses
Clinical/Imaging Follow
Up
Alternative Diagnosis
Established
Further clinical/imaging
typical for MS
MS Diagnosis
ON Typical for MS
MRI not Fulfilling Criteria
Clinical/Imaging
Follow Up
CIS

78. ON TM BS
78
Clinically Isolated Syndrome (CIS)

79. MRI brain and cervical cord (1)
with Gd
Abnormal
[conversion rate 80%] (2)
Wait till
CDMS
DMT
Normal
[conversion rate 20%] (2)
Follow up
79
Conversion of CIS to CDMS

80. 80
Conversion of CIS to CDMS

81. 81
Conversion of CIS to CDMS

82. Mar Tintore et al. Brain 2015;138:1863-1874
© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.
All rights reserved. For Permissions, please email: journals.permissions@oup.com
Conversion of CIS to CDMS

83. 83

84. PLEASE
ORAL STEROIDS

85. 85
• The ONTT was a prospective, randomized, multicenter placebo-
controlled clinical trial designed to compare the benefits of
treatment with (1) intravenous methylprednisolone (IVMP) (250 mg
administered every 6 h for 3 days followed by oral prednisone [1
mg/kg/day] for 11 days); (2) oral prednisone (1 mg/kg/day); or (3)
oral placebo in 457 patients with acute optic neuritis.
• The ONTT showed that treatment with standard-dose oral
prednisone was associated with an increased rate of new attacks of
optic neuritis.
Beck RW, Cleary PA, Anderson MM Jr, Keltner JL, Shults WT, Kaufman DI. A randomized, controlled trial of corticosteroids in the treatment of acute
optic neuritis. The Optic Neuritis Study Group. N Engl J Med. 1992 Feb 27. 326(9):581-8.
PLEASE

86. • After 5 years, the recurrence rate was
found to be higher in the oral
prednisone (1 mg/kg) group (41%)
than in those who received IVMP or
oral placebo (25%).
86
1. Costello F, Burton JM. An approach to optic neuritis: the initial presentation. Expert Rev Ophthalmol. 2013. 8(6):539–551.
2. Shams PN, Plant GT. Optic neuritis: a review. Int MS J. 2009 Sep. 16(3):82-9.
PLEASE

87. Neuro-Ophthalmology of Multiple Sclerosis
87
Opthalmological presentations of MS
Vision Ocular motility

88. Diplopia
• Horizontal
• Vertical (skew deviation)
• Mixed
• Fluctuating
Oscillopsia
Ocular Motility Disorders

89. • Supranuclear
• Nuclear
• Internuclear abnormalities
• Infranuclear or Nerve
• Nystagmus
• Vestibulo-ocular dysfunction
• Saccadic system
• Pursuit system
Ocular Motility Disorders

90. • Supranuclear (Gaze Palsies)
• Nuclear
• Internuclear abnormalities (INO,bilat INO,1.5 syndrome)
• Infranuclear or Nerve (VI: Most common, III:Partial or Complete, IV: Rare)
• Nystagmus
• Vestibulo-ocular dysfunction
• Saccadic system
• Pursuit system
Ocular Motility Disorders

91. Saccadic abnormalities
• Hypometric
• Hypermetric
• Dysmetria
• Saccadic Intrusions
– Square wave jerks
– Saccadic pulses
– Ocular flutter
Ocular Motility Disorders

92. Saccadic Dysmetria
Macrosaccadic Oscillations
Square Wave Jerks
Macro Square Wave Jerks
Ocular Flutter
From: Leigh & Zee. The Neurology of Eye Movements, F.A. Davis Company
Saccadic Oscillations

93. From: Kline & Bajandas. Neuro-ophthalmology Board Review Manual; Slack Inc
Internuclear Ophthalmoplegia:MLF Lesion

94. •Gaze evoked
•Direction changing
cerebellar
•Direction selective
vestibular
•Ataxic of INO
•Vertical (Upbeat or
downbeat)
•Rebound
•Torsional
•Acquired pendular
•Periodic alternating
•Lid nystagmus
•Superior oblique
myokymia*
Interesting but rarely localizing
*Not really a “nystagmus”
Nystagmus

95. • Congenital strabismus
• Latent nystagmus
• DVD (Dissociated Vertical Divergence)
• Convergence spasm
• Voluntary nystagmus
• Congenital or chronic IVth (FAT scan)
• Duane’s Retraction Syndrome
There are some ocular motility disturbances that have nothing to
do with MS.
Ocular Motility Disorders

96. 96
INO

97. 97
Bilateral INO : ??Pathognomonic

98. 98
One and Half syndrome

99. 99
INO: MG!!

100. 10
0
One and Half syndrome: Midbrain infarction !

101. ‫المتعدد‬ ‫التصلب‬ ‫وحدة‬–‫العيني‬ ‫قصر‬

102. ‫المتعدد‬ ‫التصلب‬ ‫وحدة‬–‫العيني‬ ‫قصر‬

103. ‫المتعدد‬ ‫التصلب‬ ‫وحدة‬–‫العيني‬ ‫قصر‬

104. ‫المتعدد‬ ‫التصلب‬ ‫وحدة‬–‫العيني‬ ‫قصر‬

105. ‫المتعدد‬ ‫التصلب‬ ‫وحدة‬–‫العيني‬ ‫قصر‬

106. 10
6

107. THANK YOU