Diagnosis and red flags in Multiple sclerosis

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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

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1.Diagnosis

Multiple Sclerosis Diagnosis

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• Diagnosis relies on clinical judgment.

• MS is extremely variable.

• There is no specific test.

• The diagnosis has dramatic implications.

Multiple Sclerosis Diagnosis

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Diagnosis of MS includes

To prove it is M.S To exclude other

diagnoses

How to diagnose MS?

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Clinical:

• History and examination.

• Evidence of CNS

involvement.

• Dissemination in space

and time.

Paraclinical:

• Neuroimaging.

• Evoked potentials.

• CSF analysis.

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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

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Magnetic resonance imaging

T1 weighted Pre & Post Contrast

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2. VEP

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Diagnostic tools

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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

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IgG index:

• [IgGCSF/albuminCSF]/[IgGserum/albuminserum]

MS patients elevated IgG index (>1.7). (normal is <0.77)

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Oligoclonal Bands in CSF

Multiple Sclerosis Diagnosis

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Diagnosis of MS includes

To prove it is M.S To exclude other

diagnoses

Mental map for diagnosis of MS

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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

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Red flags

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• 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

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• Clinical

• Lab

• Imaging

Outline

The Red Flags

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• Clinical

• Lab

• Imaging

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Clinical Red

Flags

Clinical Red Flags (Major)

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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)

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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)

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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)

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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)

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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)

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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)

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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)

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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

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• Dementia

CADASIL

• Speech disoders

Aphasia

• Stroke like events

Antiphospholipid Syndrome.

CNS vasculitis.

• Prominent psychiatric illness

Clinical Red Flags

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• Extrapyramidal disorders

Rest tremors

Dystonia

Chorea

Tics

Dyskinesia

• Steroid dependence

Neurosarcoid

CNS lymphoma

Clinical Red Flags

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• Fever at the onset.

• Dermatologic involvement , other than psoriasis.

• Endocrinologic disease other than autoimmune

thyroid disease.

Outline

The Red Flags

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• Clinical

• Lab

• Imaging

Outline

The Red Flags

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• Clinical

• Lab

• Imaging

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Laboratory

Red Flags

Laboratory Red Flags

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• CBC: Marked cell count abnormality

• High ESR

• +ve ANA

Laboratory Red Flags

CSF

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• 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

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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

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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

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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

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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.

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Imaging Red

Flags

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“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

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The Red Flags

MRI Red Flags (Major)

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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)

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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)

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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)

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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)

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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)

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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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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).

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Normal Aging

These white matter changes are classified

according to Fazekas:

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• 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.

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Infarctions

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Infarctions

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Distribution of white matter lesions

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MRI Red Flags

Diffuse/Symmetric matter involvement

Adult Onset AD Leukodystrophy

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MRI Red Flags

Diffuse/Symmetric white matter involvement

HIV Associated Neurocognitive Disorder

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Nonspecific White Matter T2 lesions

• Smoking

• Hypertension

• Diabetes

• Toxic

• Radiation

• Chemotherapy

• Congenital

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MRI Red Flags

Atypical brainstem lesions Neuro-Behçet

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MRI Red Flags

CADASIL Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

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MRI Red Flags

Primary CNS Vasculitis

Hemorrhage

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MRI Red Flags

Amyloid Angiopathy

Microhemorrhage

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MRI Red Flags

Poorly defined lesion border/ U fiber involvement

Progressive Multifocal Leukoencephalopathy

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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.

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MRI Red Flags

Leptomeningeal enhancement

Neurosarcoidosis

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MRI Red Flags

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MRI Red Flags

Increasing lesion size/persistent enhancement

One month later

Primary CNS Lymphoma

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Neurologic symptoms +

Incidental/Nonspecific brain

MRI abnormality = MS

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The Incidentals

Capillary Pontine Telengectasia

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The Incidentals

Cavernous Angioma

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The Incidentals

Intraspinal Neurenteric Cyst

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CIS RED FLAGS

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D.D. OF M.S. IN MRI

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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

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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

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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