1
Red Flags
in Multiple Sclerosis
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Amr Hasan, M.D. Associate Professor of Neurology - Cairo University
2016
Red Flags in Multiple Sclerosis
3
1.Diagnosis
Multiple Sclerosis Diagnosis
4
• Diagnosis relies on clinical judgment.
• MS is extremely variable.
• There is no specific test.
• The diagnosis has dramatic implications.
Multiple Sclerosis Diagnosis
5
Diagnosis of MS includes
To prove it is M.S To exclude other
diagnoses
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
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
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
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
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
Magnetic resonance imaging
T2 weighted images showing plaques
13
Magnetic resonance imaging
T1 weighted Pre & Post Contrast
14
15
16
2. VEP
20
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
CSF examination
22
IgG index:
• [IgGCSF/albuminCSF]/[IgGserum/albuminserum]
MS patients elevated IgG index (>1.7). (normal is <0.77)
23
Oligoclonal Bands in CSF
Multiple Sclerosis Diagnosis
24
Diagnosis of MS includes
To prove it is M.S To exclude other
diagnoses
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
The Red Flags
26
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.
Outline
The Red Flags
28
• Clinical
• Lab
• Imaging
Outline
The Red Flags
29
• Clinical
• Lab
• Imaging
30
Clinical Red
Flags
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
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
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
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
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
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
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
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
Clinical Red Flags
39
• Dementia
CADASIL
• Speech disoders
Aphasia
• Stroke like events
Antiphospholipid Syndrome.
CNS vasculitis.
• Prominent psychiatric illness
Clinical Red Flags
40
• Extrapyramidal disorders
Rest tremors
Dystonia
Chorea
Tics
Dyskinesia
• Steroid dependence
Neurosarcoid
CNS lymphoma
Clinical Red Flags
41
• Fever at the onset.
• Dermatologic involvement , other than psoriasis.
• Endocrinologic disease other than autoimmune
thyroid disease.
Outline
The Red Flags
42
• Clinical
• Lab
• Imaging
Outline
The Red Flags
43
• Clinical
• Lab
• Imaging
44
Laboratory
Red Flags
Laboratory Red Flags
45
• CBC: Marked cell count abnormality
• High ESR
• +ve ANA
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
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 .
Labs UPON red flags
48
CNS Neoplasm/ Infiltrative Disorder:
• CSF cytology and flow cytometry, CXR, CT Chest\ Abdomen\Pelvis,
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 .
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.
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
Imaging Red
Flags
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
The Red Flags
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
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
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
MRI Red Flags (Intermediate)
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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
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
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
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
WMLs differential diagnosis
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63
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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
Normal Aging
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
Infarctions
68
Infarctions
69
Distribution of white matter lesions
70
71
72
73
74
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MRI Red Flags
Diffuse/Symmetric matter involvement
Adult Onset AD Leukodystrophy
76
MRI Red Flags
Diffuse/Symmetric white matter involvement
HIV Associated Neurocognitive Disorder
77
Nonspecific White Matter T2 lesions
• Smoking
• Hypertension
• Diabetes
• Toxic
• Radiation
• Chemotherapy
• Congenital
78
MRI Red Flags
Atypical brainstem lesions Neuro-Behçet
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80
MRI Red Flags
CADASIL Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy
81
MRI Red Flags
Primary CNS Vasculitis
Hemorrhage
82
MRI Red Flags
Amyloid Angiopathy
Microhemorrhage
83
MRI Red Flags
Poorly defined lesion border/ U fiber involvement
Progressive Multifocal Leukoencephalopathy
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
MRI Red Flags
Leptomeningeal enhancement
Neurosarcoidosis
86
MRI Red Flags
87
MRI Red Flags
Increasing lesion size/persistent enhancement
One month later
Primary CNS Lymphoma
88
Neurologic symptoms +
Incidental/Nonspecific brain
MRI abnormality = MS
89
The Incidentals
Capillary Pontine Telengectasia
90
The Incidentals
Cavernous Angioma
91
The Incidentals
Intraspinal Neurenteric Cyst
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CIS RED FLAGS
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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
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
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
THANK YOU