# Demyelinating and White Matter Diseases

## Overview

### Clinical Significance

White matter diseases are common findings on brain MRI. The radiologist must distinguish demyelinating disease from small vessel ischemic disease, vasculitis, and other white matter pathologies. MRI is the primary diagnostic and monitoring modality for multiple sclerosis. Pattern recognition based on distribution, morphology, enhancement pattern, and clinical context is key.

## Multiple Sclerosis (MS)

### Epidemiology

MS is the most common demyelinating disease, with peak onset between ages 20 and 40 and a female predominance of 2-3 to 1. It results from autoimmune-mediated destruction of myelin in the central nervous system. Relapsing-remitting MS (RRMS) is the most common pattern and may progress to secondary progressive MS (SPMS).

### McDonald Criteria (2017 Revision)

The diagnosis of MS requires demonstration of **dissemination in space (DIS)** and **dissemination in time (DIT)**. DIS requires lesions in 2 or more of 4 characteristic locations: periventricular (3 or more lesions in the 2017 criteria), cortical or juxtacortical, infratentorial (brainstem, cerebellum, or spinal cord), and spinal cord. DIT is demonstrated by simultaneous enhancing and non-enhancing lesions on a single MRI, a new T2 or enhancing lesion on follow-up MRI, or the presence of CSF-specific oligoclonal bands.

### MRI Features

MS plaques appear as **T2/FLAIR hyperintense** lesions that are ovoid, well-defined, and typically 3-15 mm in size. **Periventricular lesions** are oriented perpendicular to the ventricles along the medullary veins, producing the characteristic **"Dawson fingers"** pattern on sagittal FLAIR. Lesions at the **calloseptal interface** (the undersurface of the corpus callosum) are relatively specific for MS. **Infratentorial** lesions involve the brainstem (surface of the pons, floor of the fourth ventricle) and cerebellar peduncles. **Cortical and juxtacortical** lesions involve the cortex or immediately subjacent white matter and are best seen on DIR (double inversion recovery) or 3D FLAIR. **Spinal cord** lesions are short-segment (less than 2 vertebral segments), peripheral in location, involve the dorsal or lateral columns, are often cervical, and show partial cross-sectional involvement.

### Enhancement Patterns

An active MS lesion shows **incomplete ring enhancement** (the open ring sign, with the ring open toward the gray matter side), which is characteristic of MS. Enhancement indicates active inflammation and blood-brain barrier disruption and typically lasts 2-8 weeks. Closed-ring enhancement is more suggestive of abscess or tumor.

### T1 Black Holes

Chronic T1 hypointense lesions represent severe demyelination and axonal loss and correlate with permanent disability. Acute T1 black holes may resolve, but persistent T1 black holes indicate tissue destruction.

### Central Vein Sign

T2/FLAIR lesions in MS typically have a central vein running through them, visible on SWI or T2* sequences. This is proposed as a biomarker to distinguish MS from other white matter diseases. When 40% or more of lesions show a central vein, it is highly suggestive of MS.

## Neuromyelitis Optica Spectrum Disorder (NMOSD)

### MS vs. NMOSD vs. ADEM Comparison

| Feature | MS | NMOSD | ADEM |
|---------|----|----|------|
| Course | Relapsing-remitting or progressive | Relapsing (severe attacks) | Monophasic |
| Antibody | None specific | AQP4-IgG (~80%) | None |
| Cord lesion | Short-segment (<2 vertebral segments) | LETM (>=3 segments) | Longitudinally extensive |
| Brain lesions | Dawson fingers, calloseptal, periventricular | Periependymal, area postrema | Large, poorly defined, deep gray |
| Enhancement | Open ring (incomplete) | Cloud-like | Simultaneous (same age) |
| Demographics | Young adults, F>M | F>M, non-Caucasian | Children (post-infectious) |

### Key Differences from MS

NMOSD is associated with the **aquaporin-4 (AQP4) IgG** autoantibody, which is positive in approximately 80% of cases. It has a predilection for the optic nerves and spinal cord. Attacks are more severe with less complete recovery than MS. It is more common in women and non-Caucasian populations. Treatment differs from MS, and importantly, some MS therapies worsen NMOSD.

### MRI Features

**Optic neuritis** in NMOSD is extensive, bilateral, and involves the posterior optic pathway (chiasm and optic tracts) with enhancement. **Longitudinally extensive transverse myelitis (LETM)** spans 3 or more vertebral segments (compared to less than 2 in MS) with central cord location and bright spotty lesions on T2. The **area postrema** (dorsal medulla) is a characteristic location, causing intractable hiccups and nausea. **Periependymal and diencephalic** lesions occur around the third ventricle and hypothalamus with cloud-like enhancement. Brain lesions can mimic MS but tend to follow AQP4-rich areas.

## Acute Disseminated Encephalomyelitis (ADEM)

### Key Features

ADEM is a monophasic demyelinating disease that typically occurs in children, developing 1-2 weeks after a viral illness (post-infectious) or vaccination. It presents with acute onset encephalopathy, which distinguishes it from MS (which typically lacks encephalopathy). On MRI it produces large, poorly defined, bilateral white matter lesions that often involve the deep gray matter (thalami and basal ganglia). Lesions enhance simultaneously (all of similar age, unlike MS, which shows lesions of different ages). Spinal cord involvement is longitudinally extensive (like NMOSD, unlike MS). Most patients recover, but recurrence should raise concern for MS.

## Other White Matter Diseases

### Small Vessel Ischemic Disease (SVID)

SVID is the most common cause of white matter signal abnormality in older adults. Risk factors include hypertension, diabetes, aging, and hyperlipidemia. The distribution involves periventricular caps and bands, deep white matter, and subcortical regions. Key differences from MS include involvement of the subcortical U-fibers (which MS tends to spare, though this distinction is imperfect), absence of calloseptal interface lesions, absence of the central vein sign, no enhancement (unless there is an acute lacunar infarct), and no spinal cord lesions. The Fazekas scale (0-3) is used to grade severity.

### Posterior Reversible Encephalopathy Syndrome (PRES)

PRES occurs in the context of hypertension, eclampsia, immunosuppressive drugs, or renal failure. On MRI it produces bilateral symmetric T2/FLAIR hyperintensity in the parietal-occipital regions (posterior predilection due to limited sympathetic innervation of the posterior circulation). It may also involve the frontal lobes, cerebellum, brainstem, and basal ganglia. It usually does not restrict on DWI (vasogenic edema, not cytotoxic). If DWI restriction is present, it suggests infarction and potentially irreversible injury. PRES is typically reversible with blood pressure control or removal of the offending agent.

### Progressive Multifocal Leukoencephalopathy (PML)

PML results from JC virus reactivation in immunocompromised patients (HIV, natalizumab therapy, transplant). On MRI it shows asymmetric, confluent, subcortical white matter lesions with U-fiber involvement being characteristic. It does not enhance (unless immune reconstitution inflammatory syndrome, or IRIS, develops), does not typically cause mass effect, and shows no restricted diffusion (except at the advancing edge). The clinical course is characterized by progressive deterioration and is often fatal.

### Osmotic Demyelination Syndrome (ODS)

**Central pontine myelinolysis** presents as symmetric T2 hyperintensity in the central pons with a "trident" or "bat-wing" shape, sparing the periphery and corticospinal tracts. **Extrapontine myelinolysis** shows bilateral symmetric involvement of the basal ganglia, thalami, and cerebellum. The clinical context is rapid correction of hyponatremia. DWI may show early restricted diffusion before T2 changes become apparent.

<image>A sagittal and axial FLAIR MRI panel demonstrating classic multiple sclerosis findings. Sagittal FLAIR image showing ovoid periventricular lesions oriented perpendicular to the lateral ventricles (Dawson fingers, arrows). Lesions are visible at the calloseptal interface (undersurface of the corpus callosum). Axial FLAIR image showing periventricular, juxtacortical, and deep white matter plaques. An axial post-contrast T1 image shows an active lesion with incomplete ring enhancement (open ring sign, arrow). A sagittal T2 MRI of the cervical spinal cord shows a short-segment hyperintense lesion in the dorsolateral cord.</image>

<image>A comparison MRI panel of NMOSD vs. MS spinal cord lesions. Left: Sagittal T2 MRI of the spinal cord in NMOSD showing longitudinally extensive transverse myelitis spanning more than 3 vertebral segments with central cord involvement (LETM). An axial T2 image shows the lesion occupying more than 2/3 of the cord cross-section. Right: Sagittal T2 MRI of the spinal cord in MS showing a short-segment lesion spanning less than 2 vertebral segments with peripheral/dorsal cord involvement. An axial T2 image shows the lesion occupying less than half the cord cross-section. Key distinguishing features are annotated.</image>

<image>A brain MRI comparison panel showing three common white matter disease patterns. (1) Multiple sclerosis: axial FLAIR showing discrete ovoid periventricular lesions with Dawson finger orientation and calloseptal interface lesions. (2) Small vessel ischemic disease: axial FLAIR showing confluent periventricular white matter hyperintensity (Fazekas Grade 2-3) without discrete ovoid lesions or calloseptal involvement. (3) ADEM: axial FLAIR showing large, poorly marginated, bilateral white matter and deep gray matter lesions (thalamic involvement) in a child. Each entity is labeled with its distinguishing features.</image>

## Clinical Pearls

Dawson fingers (periventricular lesions perpendicular to the ventricles on sagittal FLAIR) and calloseptal interface lesions are highly suggestive of MS and help distinguish it from small vessel ischemic disease. The open ring (incomplete ring) enhancement pattern is characteristic of demyelination, while closed ring enhancement is more concerning for abscess or tumor. NMOSD causes longitudinally extensive transverse myelitis (3 or more segments) while MS causes short-segment (less than 2 segments) cord lesions, and this distinction has critical treatment implications. PRES characteristically involves the posterior parietal-occipital regions with vasogenic edema (no DWI restriction); DWI restriction in PRES suggests infarction and worse prognosis. PML involves the subcortical U-fibers, does not enhance, and does not cause mass effect; enhancement in a PML patient suggests immune reconstitution inflammatory syndrome (IRIS). The central vein sign on SWI/T2* is emerging as a useful biomarker to distinguish MS plaques from non-specific white matter lesions, with 40% or more of lesions showing a central vein supporting MS.

## References

- Thompson AJ, et al. "Diagnosis of Multiple Sclerosis: 2017 Revisions of the McDonald Criteria." *Lancet Neurology*, 2018
- Wingerchuk DM, et al. "International Consensus Diagnostic Criteria for NMOSD." *Neurology*, 2015
- Filippi M, et al. "MRI Criteria for the Diagnosis of Multiple Sclerosis." *Lancet Neurology*, 2016
- ACR Appropriateness Criteria: Multiple Sclerosis, 2019