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KEY FACTS

Diagnostic Checklist
- Multiple sclerosis (MS) - Demyelinating disease characterized by multiple lesions disseminated in time & space - Brain lesions: Multiple T2- & FLAIR MR hyperintense foci, typically small (5-10 mm), ovoid, discrete, periventricular, & perpendicular to ventricular margins - Optic neuritis (ON): Unilateral, short segment, intraorbital; myelitis: < 2 vertebrae in length, < 50% of cross-sectional area, typically peripheral
- Acute disseminated encephalomyelitis (ADEM) - Acute demyelinating disease with encephalopathy, without NMOSD or anti-MOG associated antibodies - Characteristically arises subsequent to infection (viral respiratory) or vaccination - Brain: Ill-defined, larger T2-/FLAIR hyperintense lesions
- Neuromyelitis optica spectrum disorders (NMOSD) - Inflammatory CNS disease caused by antibodies to aquaporin-4 (AQP-4) on astrocytic end feet - ON & transverse myelitis predominate clinically - Brain: Commonly periventricular but parallel to ependymal lining; area postrema involvement is classic - ON: Bilateral, posterior predominant (including chiasm) - Myelitis: Longitudinally extensive transverse myelitis (LETM) (> 3 vertebrae), > 50% of cord cross section, central
- Anti-MOG syndromes - Acute demyelinating disease caused by antibodies to myelin oligodendrocyte glycoprotein (MOG) - Extensive clinical overlap with ADEM & NMOSD; encephalopathy in younger patients, ON in older - Brain: Similar to ADEM - ON: Bilateral anterior predominant (including optic disc) with perineural enhancement - Myelitis: LETM vs. short segment; conus involvement
- Lyme disease - 11% develop neurologic manifestations - May be accompanied by ON or other CN inflammation

TERMINOLOGY

Definitions
- Acquired demyelinating processes characterized by inflammation - Multiple sclerosis (MS) - Demyelinating disease characterized by multiple lesions disseminated in time & space - Acute disseminated encephalomyelitis (ADEM) - Acute demyelinating disease with encephalopathy, without NMOSD or anti-MOG-associated antibodies - Neuromyelitis optica spectrum disorders (NMOSD) - Inflammatory CNS disease caused by antibodies to aquaporin-4 (AQP-4) on astrocytic end feet - Clinically characterized by optic neuritis & transverse myelitis - Antimyelin oligodendrocyte glycoprotein (MOG) syndromes - Acute demyelinating disease caused by antibodies to MOG - Extensive clinical overlap with ADEM & NMOSD - Lyme disease - CNS inflammation associated with Borrelia burgdorferi infection

IMAGING

General Features
- MS - Brain: Multiple T2- & FLAIR MR hyperintense lesions, typically small (5-10 mm), ovoid, discrete - > 85% are periventricular: Callosal involvement, hemispheric white matter; perpendicular to ventricle margin in perivenular distribution - Variable enhancement: Presumed to reflect active demyelination - Nodular, diffuse, or ring-like - Can be mass-like: Tumefactive MS - Diffusion restriction in acute lesions - Diffusely abnormal ADC values - "Black holes" (due to axonal destruction) on T1 are much more likely to be seen in MS than ADEM - Optic neuritis (ON): Unilateral, short length, intraorbital - Myelitis: < 2 vertebral lengths, < 50% of cord cross section, cervical > thoracic
- ADEM - Brain: Ill-defined larger T2-/FLAIR hyperintense lesions - Lesions are more likely to be diffuse & bilateral - Frequent brainstem & thalamic involvement - ON: Less common; myelitis: Less common
- NMOSD - Brain: May have extensive lesions - Commonly periventricular but parallel - Dorsal brainstem (especially area postrema) - ON: Bilateral long segment - Posterior predominant, including chiasm - Myelitis: Longitudinally extensive transverse myelitis (LETM) (> 3 segments), typically central & > 50% circumference
- Anti-MOG syndromes - Brain: Similar in appearance to ADEM - Much less likely to involve corpus callosum - ON: Bilateral long length with perineural enhancement - Anterior predominant, including optic disc - Myelitis: LETM vs. short segment; conus often affected
- Lyme disease - Presents as meningoencephalitis - May be accompanied by ON or other cranial nerve inflammation; Bell palsy is characteristic

Imaging Recommendations

Best imaging tool
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- MR
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Protocol advice

- FLAIR MR imaging for detection
        - Postcontrast FLAIR may ↑ detection of meningeal disease
- Fat-saturated, high-resolution postcontrast orbital MR for assessment of ON
- Spine imaging with contrast & axial T2-weighted sequences

DIFFERENTIAL DIAGNOSIS

Posterior Reversible Encephalopathy Syndrome
- Subcortical vasogenic edema associated with hypertension
Viral Encephalitis
- Widely variable, but often affects white matter & deep gray nuclei
Autoimmune-Mediated Vasculitis
- Enhancing lesions spare callososeptal interface
- Reported in COVID-19 infection
- Beaded angiogram appearance
Leukodystrophies
- Patterns vary by metabolic defect - Metachromatic leukodystrophy, Alexander disease, X-linked adrenoleukodystrophy
Toxin-Induced Brain Injury
- Carbon monoxide or methanol poisoning
- Bilateral symmetric basal ganglia lesions - Accompanying subcortical lesions in methanol poisoning

PATHOLOGY

General Features

Etiology

- MS
        - Possibly viral-incited autoimmune reaction in genetically susceptible individuals
                  - No "trigger" identified
        - Activated T cells attack myelinated axons
        - B cells, antibodies, macrophages, & microglia all contribute to lesions
        - Cox-2, iNOS may cause excitotoxic death of oligodendrocytes
- ADEM
        - Autoimmune-mediated demyelination
        - Characteristically arises subsequent to infection (viral respiratory) or vaccination
- NMOSD
        - Antibodies to aquaporin-4 (AQP-4) channels on astrocytic end feet
                  - Technically not demyelinating
        - AQP-4 is dispersed throughout CNS
                  - Highly expressed in optic nerves & spinal cord
        - AQP-4 antibodies are more highly expressed in peripheral blood than CSF
- Anti-MOG syndromes: Antibodies to MOG
        - MOG is CNS specific protein expressed on outer surface of myelin sheath
- Lyme disease
        - Caused by spirochete *Borrelia burgdorferi*
        - Tick-borne disease; deer tick (Ixodes scapularis) or Western black-legged tick (Ixodes pacificus)

Staging, Grading, & Classification
- Major clinical subtypes of MS - Relapsing-remitting (85% initial presentation) - Primary-progressive, a.k.a. chronic progressive (5-10%) - Progressive from start - Secondary-progressive, a.k.a. relapsing progressive - By 10 years 50% & by 25 years 90% of relapsing-remitting patients enter secondary-progressive phase - Progressive-relapsing - Rare; defined as progressive disease with clear acute relapses ± full recovery - Periods between relapses are characterized by continuing disease progression - Clinically isolated syndrome (CIS): Single episode > 24 hours; vast majority progress to MS after number of years
- MS variants/subtypes - Malignant: Younger patients, febrile prodrome, clinically fulminant, death in months - Schilder type ("diffuse sclerosis"): Extensive, confluent, asymmetric demyelination in bilateral supra-/infratentorial parenchyma - Baló type ("concentric sclerosis"): Large lesions with alternating zones of demyelinated/myelinated white matter
Gross Pathologic & Surgical Features
- Acute MS: Poorly delineated, yellowish-white, periventricular plaques
- Chronic MS: Gray, granular, well-demarcated plaques ± generalized volume loss
Microscopic Features
- MS - Perivenous demyelination & oligodendrocyte loss - Active: Foamy macrophages with myelin fragments, lipids; reactive astrocytes + perivascular inflammation; some are hypercellular with atypical reactive astrocytes & mitoses (mimics tumor) - Chronic: Marked loss of myelin & oligodendrocytes; dense astrogliosis; minimal/no perivascular inflammation - Axonal transection - CSF positive for oligoclonal bands

CLINICAL ISSUES

Presentation

Most common signs/symptoms

- MS
        - Variable
        - Initially impaired/double vision of acute ON (50% with positive MR develop MS)
        - Weakness, numbness, tingling, gait disturbances
        - ↓ sphincter control, blindness, paralysis, dementia
        - Cranial nerve palsies; usually multiple, 1-5% isolated (CNV & VI are most common)
        - Spinal cord symptoms in 80%
- ADEM
        - Cranial nerve palsies, encephalopathy, headache 2 days to 4 weeks after prodrome
        - Seizures in 10-35%
        - Monophasic illness
                  - Can recur in small percentage of cases (controversial)
- NMO
        - Rapid onset of vision loss
        - Subsequent spinal cord symptoms, paralysis
- Lyme disease
        - Stereotypical expanding rash around tick bite: Erythema chronicum migrans
                  - Infrequently recognized
        - Bell palsy, meningitis, arthralgias

Demographics
- Estimated 2,500,000 have MS worldwide - MS most often occurs in temperate climates - Most common disabling CNS disease of young adults: 1 in 1,000 in Western world
- 3-5% of MS is diagnosed before age 15 years
- 20% of childhood MS is initially diagnosed as ADEM
- 1/3 of acute demyelinating disease in children is anti-MOG
Natural History & Prognosis
- MS: 45% of MS patients are not severely affected & are nearly normal - > 80% with "probable" MS & positive MR progress to clinically definite MS
- ADEM: Characteristically monophasic - Recurrence suggests anti-MOG
- Anti-MOG syndromes are more frequently seen in young - Encephalopathy is more common in younger patients, ON in older
- 90% of NMOSD in pediatrics have relapsing disease
- Lyme disease: 11% develop neurologic manifestations
Treatment
- MS & NMOSD are both treated with immune-modulating therapy
- ADEM is typically treated with high-dose steroids - Alternative treatments include IVIg & plasma exchange
- Anti-MOG syndromes respond quickly to steroid & IVIg treatment
- Lyme is treated with antibiotics - No evidence that antibiotic therapy alters natural history

DIAGNOSTIC CHECKLIST

Image Interpretation Pearls
- 95% with definite MS clinically have positive MR

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References

Selected References

Images

Selected Images

Sagittal T2 MR in a 9-year-old with optic neuritis shows multiple ill-defined hyperintensities in the medulla & cervical cord. Subsequent serum testing revealed antibodies to aquaporin 4, confirming a diagnosis of neuromyelitis optica spectrum disorders (NMOSD).

Axial T1 C+ FS MR through the orbits shows diffuse bilateral optic nerve enhancement in this 9-year-old with vision loss. Clinical features were suggestive of NMOSD, but CSF analysis confirmed anti-myelin oligodendrocyte glycoprotein (MOG) disease.

Axial NECT in a 16-year-old with progressive left-sided weakness after minor trauma shows a large, low-attenuation white matter lesion in the anterior right frontal lobe & a smaller one near the right motor strip .

Sagittal T1 C+ MR in the same patient shows the borders of the large lesion nearest to the cortex to be nonenhancing as compared to the other margins . This open ring appearance can help distinguish tumefactive MS from abscess or neoplasm (which more typically have complete ring enhancement).

Additional Images

Sagittal graphic illustrates MS plaques involving the corpus callosum, pons, & spinal cord. Note the characteristic perpendicular orientation of the lesions at the callososeptal interface along penetrating venules.

Sagittal FLAIR MR shows numerous MS plaques with typical perpendicular orientation at the callososeptal interface along penetrating venules ("Dawson fingers") as well as in the subcortical white matter.

Sagittal FLAIR MR shows perpendicular callosal/pericallosal MS plaques with hyperintense rims & hypointense centers (with corresponding hypointensities also demonstrated on T1 as "black holes," not shown). Note an additional posterior fossa lesion .

Axial T1 C+ MR demonstrates multiple nodular, enhancing multiple sclerosis plaques . Note the common periventricular location with perpendicular orientation as well as the involvement of subcortical white matter.

Axial FLAIR MR shows confluent multiple sclerosis plaques in commonly seen periventricular locations.

Axial FLAIR MR in a 9-year-old patient with altered mental status & hyperreflexia shows ill-defined, hyperintense lesions in the thalami , basal ganglia , & insula . Involvement of the deep nuclei is a relatively common feature of acute disseminated encephalomyelitis.

Axial FLAIR MR shows large lesions in the thalamus & basal ganglia in this 16-year-old with a headache & weakness 2 weeks after a viral illness. Acute disseminated encephalomyelitis will frequently affect deep gray matter structures.

Coronal FLAIR MR in a 12-year-old patient with neuromyelitis optica & bladder dysfunction shows large lesions extending across the corpus callosum & left cerebral peduncle .

Axial NECT in a 14-year-old patient with vomiting shows a nonspecific, low-attenuation lesion in the left posterior frontal subcortical white matter.

Axial FLAIR MR in the same patient acquired the next day shows several ovoid MS plaques . Active lesions will also show contrast enhancement & restricted diffusion.

Axial FLAIR MR in a 14-year-old with MS shows multiple ovoid lesions oriented perpendicular to the long axis of the lateral ventricles with hazy ↑ signal intensity in the white matter between them.

Axial T2 MR in a 17-year-old with Baló concentric sclerosis .

Sagittal T1 C+ FS MR shows an enhancing MS lesion in the dorsal aspect of the cervical cord . Approximately 2/3 of spinal cord MS lesions are found in the cervical cord. Typical features include a dorsal intramedullary lesion spanning < 2 vertebral segments in length.

Axial FLAIR MR shows numerous peripheral white matter & cortical lesions that exhibited robust contrast enhancement (not shown) in an 18-year-old woman with malignant (Marburg) MS. The patient presented with a 2-week history of behavioral changes & leg pain & died 3 weeks after presentation. The autopsy showed typical demyelinating pathology.

Axial T1 C+ FS MR in a patient with MS shows ring-enhancing masses of active demyelination. The rings of enhancement are incomplete with each ring defect pointing towards an adjacent cortex.

Coronal T1 C+ MR shows a superficial hypointense mass in the left parasagittal posterior frontal region with a peripheral crescent of incomplete or "horseshoe" enhancement . This enhancement pattern is classic for tumefactive demyelinating disease, most commonly MS.

Axial FLAIR MR shows a case of proven tumefactive MS with extensive surrounding white matter edema . Note that the imaging features present in this case could also be seen with neoplasm.

Long TE MRS in a case of tumefactive MS reveals elevated choline , ↓ NAA , & a lactate doublet . These MRS findings could be consistent with acute demyelination & probably reflect a combination of membrane disruption, neuronal loss or dysfunction, & inflammation. Note that the MRS findings in MS are not specific. The spectral pattern of demyelination & low-grade neoplasms can be similar & should therefore be interpreted cautiously.

Axial T1 C+ MR shows numerous enhancing MS plaques that were present throughout the infratentorial & supratentorial brain. MS lesions may show homogeneous enhancement but may also exhibit ring or incomplete ring patterns of enhancement.

32 KiB Raw Blame History

KEY FACTS

Diagnostic Checklist

TERMINOLOGY

Definitions

IMAGING

General Features

Imaging Recommendations

Best imaging tool

Protocol advice

DIFFERENTIAL DIAGNOSIS

Toxin-Induced Brain Injury

PATHOLOGY

General Features

Etiology

Staging, Grading, & Classification

Gross Pathologic & Surgical Features

Microscopic Features

CLINICAL ISSUES

Presentation

Most common signs/symptoms

Demographics

Natural History & Prognosis

Treatment

DIAGNOSTIC CHECKLIST

Image Interpretation Pearls

References

Selected References

Images

Selected Images

Additional Images

32 KiB

Raw Blame History