this presenttion focuses on Diagnosis and red flags in Multiple sclerosis clinical . lab and imaging Diagnosis and red flags in Multiple sclerosis

1. 1
Red Flags
in Multiple Sclerosis

2. Amr Hasan, M.D.
Associate Professor of Neurology - Cairo University
2016
Red Flags in Multiple Sclerosis

3. 3
1.Diagnosis

4. Multiple Sclerosis Diagnosis
4
• Diagnosis relies on clinical judgment.
• MS is extremely variable.
• There is no specific test.
• The diagnosis has dramatic implications.

5. Multiple Sclerosis Diagnosis
5
Diagnosis of MS includes
To prove it is M.S
To exclude other
diagnoses

6. How to diagnose MS?
6
Clinical:
• History and examination.
• Evidence of CNS
involvement.
• Dissemination in space
and time.
Paraclinical:
• Neuroimaging.
• Evoked potentials.
• CSF analysis.

7. 7

8. Diagnostic Criteria
• Dawson criteria: 1916
• Schumacher criteria: 1965
• Poser criteria: 1983
• McDonald criteria: 2001
• McDonald criteria: 2005
• McDonald criteria: 2010
All criteria require dissemination in time and space

9. Summarized Diagnostic Criteria
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. Rule out other explanations!
2010
2014

10. Diagnostic Criteria 2005
• Incorporate use of MRI
• Clinically Isolated Syndrom + MRI
Dissemination in space + MRI
Dissemination on time =
Earlier MS Diagnosis
August
DIS
DIT
November

11. New Diagnostic Criteria 2010
• Incorporate use of MRI
• Clinically Isolated Syndrom + MRI
Dissemination in space + MRI
Dissemination on time =
Earlier MS Diagnosis
August
DIS
DIT
August

13. Magnetic resonance imaging
T2 weighted images showing plaques
13

14. Magnetic resonance imaging
T1 weighted Pre & Post Contrast
14

15. 15

16. 16
2. VEP

20. 20

21. Diagnostic tools
21
CSF examination:
• Abnormal in 85% to 90% of patients with MS.
• Elevated total IgG, an elevated IgG ratio, an increased IgG synthesis
rate,
• Presence of two or more oligoclonal bands in the CSF that are not
present in a simultaneously drawn serum sample

22. CSF examination
22
IgG index:
• [IgGCSF/albuminCSF]/[IgGserum/albuminserum]
MS patients elevated IgG index (>1.7). (normal is <0.77)

23. 23
Oligoclonal Bands in CSF

24. Multiple Sclerosis Diagnosis
24
Diagnosis of MS includes
To prove it is M.S
To exclude other
diagnoses

25. Mental map for diagnosis of MS
25
Clinical/Paraclinical/Imaging
Typical for MS
Fulfills Criteria
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
Typical for MS
not Fulfilling Criteria
Clinical/Imaging Follow
Up

26. The Red Flags
26

27. Red flags
27
• Major red flags point fairly definitively to a non-MS diagnosis
• Intermediate red flags point to poor agreement and uncertainty
among raters about the weighting of the flag for differential
diagnosis in MS
• Minor red flags suggest that a disease other than MS should be
considered and fully explored, but an MS diagnosis is not excluded.

28. Outline
The Red Flags
28
• Clinical
• Lab
• Imaging

29. Outline
The Red Flags
29
• Clinical
• Lab
• Imaging

30. 30
Clinical Red
Flags

31. Clinical Red Flags (Major)
31
Bone lesions 30 Histiocytosis;
Lung involvement 30
Sarcoidosis;
Lymphomatoid granulomatosis
Multiple cranial neuropathies or
polyradiculopathy
30
Chronic meningitis, including sarcoidosis and
tuberculosis;
Lyme disease
Peripheral neuropathy 30
B12 deficiency; adrenoleukodystrophy;
metachromatic leukodystrophy,
Lyme disease
Tendon xanthomas 30 Cerebrotendinous xanthomatosis

32. Clinical Red Flags (Major)
32
Cardiac disease 29
Multiple cerebral infarcts; brain abscesses
with endocarditis or right to left cardiac
shunting
Myopathy 29
Mitochondrial encephalomyopathy (e.g.,
MELAS); Sjögren's syndrome
Renal involvement 29
Vasculitis; Fabry disease, systemic lupus
erythematosus

33. Clinical Red Flags (Major)
33
Extrapyramidal features 28
Whipple's disease; multisystem atrophy;
Wilson's disease
Livedo reticularis 28
Antiphospholipid antibody syndrome;
systemic lupus erythematosus; Sneddon's
syndrome
Retinopathy 28
Mitochondrial encephalomyopathy; Susac,
and other vasculitides (retinal infarction);
neuronal ceroid lipofuscinosis
Diabetes insipidus 28
Sarcoidosis; histiocytosis; neuromyelitis
optica
Increase serum lactate level 27 Mitochondrial disease

34. Clinical Red Flags (Major)
34
Hematological manifestations 27
Thrombotic thrombocytopenic purpura;
vitamin B12 deficiency; Wilson's disease
(hemolytic anemia); copper deficiency
Mucosal ulcers 27 Behçet's disease
Myorhythmia 27 Whipple's disease
Hypothalamic disturbance 26
Sarcoidosis; neuromyelitis optica;
histiocytosis
Recurrent spontaneous abortion
or thrombotic events
26
Antiphospholipid antibody syndrome;
thrombotic thrombocytopenic purpura;
metastatic cancer with hypercoagulable
state

35. Clinical Red Flags (Major)
35
Rash 26
Systemic lupus erythematosus; T-cell
lymphoma; Lyme disease, Fabry disease
Arthritis, polyarthalgias, myalgias 26
Systemic lupus erythematosus; Lyme disease;
fibromyalgia
Amyotrophy 25
Amyotrophic lateral sclerosis; syringomyelia;
polyradiculpathy
Headache or meningismus 25
Venous sinus thrombosis; chronic meningitis;
lymphoma or glioma, vasculitis, systemic
lupus erythematosus
Persistently monofocal
manifestations
24
Structural lesion (e.g., Chiari
malformation); cerebal neoplasm

36. Clinical Red Flags (Intermediate)
36
Sicca syndrome 23 Sjögren's syndrome
Gastrointestinal
symptoms
22
Whipple's disease; celiac disease and other
malabsorptive states that lead to B12 or copper
deficiency
Loss of hearing 21 Susac's syndrome; glioma; vertebrobasilar infarction
Fulminant course 20
Thrombotic thrombocytopenic purpura; intravascular
lymphoma; acute disseminated encephalomyelitis
Increase serum ACE level 20 Sarcoidosis; histiocytosis
Prominent family history 19
Depending on pattern of inheritance suggested by family
history: hereditary spastic paraparesis; leukodystrophy;
Wilson's disease; mitochondrial disorder; CADASIL
Constitutional symptoms 19 Sarcoidosis; Whipple's disease, vasculitis

37. Clinical Red Flags (Intermediate)
37
Progressive ataxia alone 18
Multisystem atrophy; hereditary spinocerebellar ataxia;
paraneoplastic cerebellar syndrome
Neuropsychiatric
syndrome
1 7
Susac's syndrome; systemic lupus erythematosus; Wilson's
disease, GM2 gangliosidosis
Seizure 16 Whipple's disease; vasculitis; metastases
Uveitis 15 Sarcoidosis; lymphoma; Behcet's disease
Pyramidal motor
involvement alone
13
Primary lateral sclerosis variant of ALS; hereditary spastic
paraparesis
Gradually progressive
course from onset
13
HTLV-1 associated myelopathy; adrenomyeloneuropathy;
adrenoleukodystrophy; metachromatic leukodystrophty,
B12 deficiency

38. Clinical Red Flags (Minor)
38
Brainstem syndrome 7
Pontine glioma; cavernous angioma;
vertebrobasilar ischemia
Myelopathy alone 9
Chiari type 1 malformation; cord compression
including cervical spondylosis; B12 or copper
deficiency; HTLV1
Onset before age 20 10
Mitochondrial encephalomyopathy;
leukodystrophy; Friedrich's ataxia
Abrupt onset 11
Cerebral infarction; cerebral hemorrhage; cerebral
venous sinus thrombosis
Onset after age 50 12
Cerebral infarction; amyloid angiopathy;
lymphoma

39. Clinical Red Flags
39
• Dementia
 CADASIL
• Speech disoders
 Aphasia
• Stroke like events
 Antiphospholipid Syndrome.
 CNS vasculitis.
• Prominent psychiatric illness

40. Clinical Red Flags
40
• Extrapyramidal disorders
 Rest tremors
 Dystonia
 Chorea
 Tics
 Dyskinesia
• Steroid dependence
 Neurosarcoid
 CNS lymphoma

41. Clinical Red Flags
41
• Fever at the onset.
• Dermatologic involvement , other than psoriasis.
• Endocrinologic disease other than autoimmune
thyroid disease.

42. Outline
The Red Flags
42
• Clinical
• Lab
• Imaging

43. Outline
The Red Flags
43
• Clinical
• Lab
• Imaging

44. 44
Laboratory
Red Flags

45. Laboratory Red Flags
45
• CBC: Marked cell count abnormality
• High ESR
• +ve ANA

46. Laboratory Red Flags
CSF
46
• Cell count: >50 White blood cells
 CNS Lymphoma
 CNS vasculitis
• Cell differential: Neutrophilic predominance
 CNS Whipple
 CNS Lupus
• Protein: Significant elevation(>100 mg/dl)
 Neurosarcoid
 Spinal stenosis
• Glucose: Low glucose(<2/3 serum glucose)
 Neurosarcoid
 CNS Lymphoma

47. Labs UPON red flags
47
CNS Inflammatory/Autoimmune Disease:
• ANA,CRP, Anti DS DNA,C3,C4, ANCA panel, Chest CT, eye exam,
conjunctival biopsy, Pathergy skin test (Behcet's), Skin biopsy
if suspicious rash present, CTA, angiogram .
CNS Infection:
• Brucella antibodies, HIV test, HTLV1, and CSF antibodies (if isolated
myelopathy with a lesion on spinal MRI), ESR, small bowel biopsy
for whipple .

48. Labs UPON red flags
48
CNS Neoplasm/ Infiltrative Disorder:
• CSF cytology and flow cytometry, CXR, CT Chest AbdomenPelvis,
Pelvic ultrasound, Mammogram, LDH, skeletal series, bone scan,
Brain biopsy.
CNS vasculopathy/Ischemic Disease:
• Notch3 mutations in CADASIL , MRA, CTA, standard angiogram,
thrombophilia panel, Lupus anticoagulant .

49. Labs UPON red flags
49
Dysmyelinating/ Metabolic Disorders:
• Lumbar puncture
• EMG/NCVs
• biochemical studies
• buccal or rectal mucosa biopsy for electron microscopy if neuronal
ceroid lipofuscinosis (NCL) suspected
• Brain biopsy (rarely needed): fingerprint profiles, curvilinear and
rectilinear bodies by E.M. in NCL oligodendrocytes; diffuse white
matter gliosis by light microscopy in NCL.

50. Labs UPON red flags
50
Urine/blood for biochemical studies, including levels of:
• WBC arylsulfatase A, Very long chain fatty, Fasting arterial lactate,
Quantitative plasma amino acid and Urine organic acid analyses.
Nutritional deficiency/Toxicity:
• Vitamin B12, Copper and Zinc Levels, Ceruloplasmin, Folate, Heavy
metal screen.

51. 51
Imaging Red
Flags

52. 52
“The most common reason for falsely
attributing a patient’s symptoms to
multiple sclerosis is faulty
interpretation of the magnetic
resonance imaging.”
Famous Dictum
Loren A. Rolak
2007

53. 53
The Red Flags

54. MRI Red Flags (Major)
54
Cerebral venous sinus
thrombosis
30
Behçet's disease; vasculitis; chronic meningitis,
antiphospholipid or anticardiolipin antibody syndromes
Cortical infarcts 29
Embolic disease; thrombotic thrombocytopenic purpura;
vasculitis
Hemorrhages/microhemo
rrhages
29
Amyloid angiopathy; Moya Moya disease; CADASIL;
vasculitis
Meningeal enhancement 29
Chronic meningitis; sarcoidosis; lymphomatosis;
CNS vasculitis

55. MRI Red Flags (Major)
55
Calcifications on CT
scans
28 Cysticercosis; toxoplasmosis, mitochondrial disorders
Selective involvement of
the anterior temporal and
inferior frontal lobe
27 CADASIL
Lacunar infarcts 27
Hypertensive ischemic disease; CADASIL; Susac
syndrome
Persistent Gd-
enhancement and
continued enlargement of
lesions
27 Lymphoma; glioma; vasculitis; sarcoidosis

56. MRI Red Flags (Major)
56
Simultaneous
enhancement of all lesions
26 Vasculitis; lymphoma; sarcoidosis
T2-hyperintensity in the
dentate nuclei
26 Cerebrotendinous xanthomatosis
T1-hyperintensity of the
pulvinar
25 Fabry disease; hepatic encephalopathy; manganese toxicity
Large and infiltrating
brainstem lesions
24 Behçet's disease; pontine glioma
Predominance of lesions
at the cortical/subcortical
junction
23
Embolic infarction; vasculitis; progressive multifocal
leukoencephalopathy

57. MRI Red Flags (Intermediate)
57
Hydrocephalus 23
Sarcoidosis or other chronic meningitis;
lymphoma or other CNS neoplasm
Punctiform parenchymal enhancement 23 Sarcoidosis; vasculitis
T2-hyperintensities of U-fibers at the vertex,
external capsule and insular regions
22 CADASIL
Regional atrophy of the brainstem 21
Behçet's disease; adult onset Alexander's
disease
Diffuse lactate increase on brain MRS 21 Mitochondrial disease
Marked hippocampal and amygdala atrophy 21 Hyperhomocystinemia
Symmetrically distributed lesions 20 Leukodystrophy
T2-hyperintensities of the basal ganglia,
thalamus and hypothalamus
20
Behçet's disease; mitochondrial
encephalomyopathies; Susac's
syndrome; acute disseminated
encephalomyelitis

58. MRI Red Flags (Intermediate)
58
Diffuse abnormalities in the
posterior columns of the cord
20
B12 deficiency; copper deficiency;
paraneoplastic disorder
Lesions across GM/WM
boundaries
19
Hypoxic-ischemic conditions;
vasculitis; systemic lupus erythematosus
T2-hyperintensities of the
temporal pole
19 CADASIL
Complete ring enhancement 18 Brain abscess; glioblastoma; metastatic cancer
Central brainstem lesions 17
Central pontine myelinolysis; hypoxicischemic
conditions; infarct

59. MRI Red Flags (Intermediate)
59
Predominant brainstem and
cerebellar lesions
1 7 Behçet's disease; pontine glioma
Lesions in the center of CC,
sparing the periphery
1 7 Susac's syndrome
Dilation of the Virchow-Robin
spaces
15
Hyperhomocystinemia;
primary CNS angiitis
Cortical/subcortical lesions
crossing vascular territories
14
Ischemic leukoencephalopathy; CADASIL;
vasculitis

60. MRI Red Flags (Intermediate)
60
Large lesions with absent or rare
mass effect and enhancement
1 3 Progressive multifocal leukoencephalopathy
No “occult” changes in the NAWM 1 3 Lyme disease, isolated myelitis, CADASIL
No enhancement 8
Progressive multifocal leukoencephalopathy; ischemic
lesions; metachromatic leukodystrophy
No optic nerve lesions 9
Metastatic carcinoma; gliomatosis cerebri;
toxoplasmosis
No spinal cord lesions 10
Multiple infarcts; vasculitis; progressive multifocal
leukoencephalopathy
Large lesions 11
Glioblastoma; lymphoma; progressive multifocal
leukoencephalopathy
No T1 hypointense lesions (black
holes)
11
Ischemic degenerative leukoencephalopathy;
progressive multifocal leukoencephalopathy
Marked asymmetry of WM lesions 12 Glioblastoma; lymphoma; cerebral infarction

61. WMLs differential diagnosis
61

62. 62

63. 63

64. 64
Normal Aging
• Periventricular caps
and bands
• Mild atrophy with
widening of sulci and
ventricles
• Punctate and
sometimes even
confluent lesions in the
deep white matter
(Fazekas I and II).

65. 65
Normal Aging

66. These white matter changes are classified
according to Fazekas:
66
• Mild - punctate WMLs: Fazekas I)
• Moderate - confluent WMLs: Fazekas II - in the deep white
matter can be considered normal in aging.
• Severe - extensive confluent WMLs: Fazekas III - always
abnormal.

67. 67
Infarctions

68. 68
Infarctions

69. 69
Distribution of white matter lesions

70. 70

71. 71

72. 72

73. 73

74. 74

75. 75
MRI Red Flags
Diffuse/Symmetric matter involvement
Adult Onset AD Leukodystrophy

76. 76
MRI Red Flags
Diffuse/Symmetric white matter involvement
HIV Associated Neurocognitive Disorder

77. 77
Nonspecific White Matter T2 lesions
• Smoking
• Hypertension
• Diabetes
• Toxic
• Radiation
• Chemotherapy
• Congenital

78. 78
MRI Red Flags
Atypical brainstem lesionsNeuro-Behçet

79. 79

80. 80
MRI Red Flags
CADASIL
Cerebral Autosomal Dominant
Arteriopathy with Subcortical Infarcts
and Leukoencephalopathy

81. 81
MRI Red Flags
Primary CNS Vasculitis
Hemorrhage

82. 82
MRI Red Flags
Amyloid Angiopathy
Microhemorrhage

83. 83
MRI Red Flags
Poorly defined lesion border/ U fiber involvement
Progressive Multifocal Leukoencephalopathy

84. 84
Tumefactive MS
• Post-gadolinium, there may
be some peripheral
enhancement, often with an
incomplete ring.
• These lesions can be
distinguished from gliomas or
intraparenchymal abscesses,
which typically have a
closed-ring enhancement.

85. 85
MRI Red Flags
Leptomeningeal enhancement
Neurosarcoidosis

86. 86
MRI Red Flags

87. 87
MRI Red Flags
Increasing lesion size/persistent enhancement
One month later
Primary CNS Lymphoma

88. 88
Neurologic symptoms +
Incidental/Nonspecific brain
MRI abnormality = MS

89. 89
The Incidentals
Capillary Pontine Telengectasia

90. 90
The Incidentals
Cavernous Angioma

91. 91
The Incidentals
Intraspinal Neurenteric Cyst

92. 92
CIS RED FLAGS

93. 93

94. 94

95. 95

96. D.D. OF M.S. IN MRI
96
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

97. D.D. OF M.S. IN MRI
97
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

98. Mental map for diagnosis of MS
98
Clinical/Paraclinical/Imaging
Typical for MS
Fulfills Criteria
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
Typical for MS
not Fulfilling Criteria
Clinical/Imaging Follow
Up

99. THANK YOU