Multiple sclerosis (MS) is the prototypic inflammatory demyelinating disease of the central nervous system. Its pathology — the demyelinated plaque — gives the disease its name (sclerosis = scarring; multiple = many lesions disseminated in space; and clinically, in time). The lesion is at once the substrate of the patient’s symptoms, the target of imaging, and the focus of therapy. Modern understanding has refined the classical view: MS is a heterogeneous disease in which plaques differ by stage (acute, chronic active, chronic inactive), by location, by histologic pattern (Lucchinetti patterns I-IV), and by underlying mechanism. This page covers MS pathology, plaque biology, and the spectrum of MS subtypes.

The MS Plaque

Gross Pathology

  • Sharply demarcated areas of demyelination in white matter.
  • Variable size, shape, distribution.
  • Predilection sites: periventricular, corpus callosum, optic nerves, brainstem (especially MLF), spinal cord (cervical), juxtacortical.
  • Color: pink-tan in active plaques; gray and depressed in chronic plaques.
  • “Dawson’s fingers”: periventricular plaques perpendicular to ventricles, characteristic of MS.

Histologic Stages

Acute Active Plaque

  • Foamy macrophages throughout the lesion containing LFB-positive myelin debris.
  • Perivascular lymphocytic inflammation (CD8+ predominant; some B cells, plasma cells).
  • Reactive astrogliosis at margins.
  • Demyelination throughout the lesion area.
  • Axons relatively preserved early; axonal injury increases with age and chronicity.

Chronic Active Plaque (“Smouldering” or “Rim-Active”)

  • Inactive demyelinated center.
  • Active inflammation and demyelination at margin (“hot rim”).
  • Macrophages and microglia at the expanding edge.
  • Iron deposition at the rim (visible on SWI as “iron rim sign”).
  • Distinctive of progressive MS.

Chronic Inactive Plaque

  • Sharply demarcated demyelination.
  • No active inflammation; sparse macrophages.
  • Reactive astrogliosis.
  • Axonal loss often substantial.
  • Sometimes partial remyelination (“shadow plaques”) — thinned, pale myelin.

Special Stains in MS Plaques

  • LFB: demyelination (pale areas).
  • LFB-PAS: distinguishes myelin debris in macrophages from other phagocytic material.
  • Bielschowsky: preserved axons in acute plaques; axonal damage in chronic.
  • Neurofilament IHC: more sensitive axonal assessment.
  • CD68: macrophages.
  • CD3, CD8, CD20: lymphocytic subsets.

Distribution of MS Plaques

White Matter

  • Periventricular (Dawson’s fingers).
  • Corpus callosum.
  • Optic nerves.
  • Brainstem (especially MLF, brainstem reticular formation).
  • Cerebellar peduncles.
  • Spinal cord (cervical > thoracic).
  • Juxtacortical (U-fiber region).

Cortical Plaques (Often Underrecognized)

Three patterns:

  • Leukocortical (type I): spanning gray-white junction.
  • Intracortical (type II): within cortex.
  • Subpial (type III): from pia inward; band-like. Common in progressive MS; underrecognized on conventional MRI.

Cortical demyelination correlates strongly with cognitive impairment in MS.

Lucchinetti Patterns (Heterogeneity of MS Plaque)

  • Pattern I: macrophage-mediated; T-cell and macrophage predominant.
  • Pattern II: antibody and complement-mediated; immunoglobulin and complement deposition at sites of myelin destruction. Likely responsive to plasmapheresis.
  • Pattern III: “dying back oligodendrocytopathy”; oligodendrocyte apoptosis with selective loss of myelin-associated glycoprotein. Distinguished by preferential loss of MAG over PLP in early lesions. Hypoxia-induced?
  • Pattern IV: primary oligodendrocyte degeneration; oligodendrocyte loss preceding demyelination. Rare; primarily white males with primary progressive course.

The biological heterogeneity may explain variable treatment responses.

MS Subtypes

Relapsing-Remitting MS (RRMS)

  • Most common (85% at onset).
  • Discrete relapses (lesion formation) with intercurrent remission.
  • Imaging shows active and chronic plaques.
  • Substantial response to DMTs (disease-modifying therapies).

Secondary Progressive MS (SPMS)

  • Evolution from RRMS after 10-20 years.
  • Continuous progression with or without superimposed relapses.
  • Pathology dominated by chronic active plaques + cortical demyelination + diffuse white matter damage.
  • Less response to traditional DMTs.

Primary Progressive MS (PPMS)

  • ~10-15% of patients.
  • Progressive from onset, no clear relapses.
  • Often older at onset (40s), more spinal cord predominance.
  • Pathology: less inflammation than RRMS; more axonal loss, cortical demyelination, slowly expanding chronic active plaques.
  • Ocrelizumab approved for PPMS.

Marburg Variant

Rare; fulminant acute MS variant with rapid progression to death. Pathology: massive demyelination, severe inflammation, sometimes pseudo-tumor effect.

Baló Concentric Sclerosis

Concentric rings of demyelinated and preserved myelin, like tree rings. Rare; distinctive MRI appearance.

Schilder Disease

Diffuse cerebral sclerosis; rare; often pediatric; sometimes confused with adrenoleukodystrophy.

Tumefactive MS

Large, mass-like demyelinating lesion mimicking tumor. Imaging: ring enhancement (often incomplete “open ring”), restricted diffusion at rim, mass effect.

Diagnostic Workup

  • Clinical: relapsing-remitting symptoms suggestive of CNS demyelination.
  • MRI: typical lesions (Dawson’s fingers, juxtacortical, infratentorial, spinal cord).
  • CSF: oligoclonal bands (OCBs) in CSF not serum — supports MS diagnosis. Elevated IgG index.
  • 2017 McDonald criteria + 2024 update: dissemination in space + dissemination in time.
  • Exclude mimics: NMO (AQP4-IgG), MOGAD (MOG-IgG), neurosarcoidosis, vasculitis, ADEM, infections, leukodystrophies.

The Progressive MS Problem

Progressive MS pathology differs from RRMS:

  • Less perivascular inflammation behind a closed BBB.
  • More compartmentalized inflammation in meninges (tertiary lymphoid follicles) and around chronic active plaques.
  • Cortical demyelination prominent.
  • Diffuse white matter axonal damage.
  • Neurodegeneration with neuronal loss.

This explains relative resistance to standard immunomodulatory therapies and the search for neuroprotective and remyelinating treatments.

Modern Therapeutic Targets

  • Interferons, glatiramer (older).
  • Oral DMTs: fingolimod, dimethyl fumarate, teriflunomide.
  • Monoclonal antibodies: natalizumab (anti-α4 integrin; blocks α4β1/α4β7-mediated leukocyte trafficking — the CNS-relevant interaction is α4β1/VLA-4 with VCAM-1 at the BBB), ocrelizumab/ofatumumab (anti-CD20), alemtuzumab (anti-CD52), rituximab.
  • BTK inhibitors: tolebrutinib, fenebrutinib — under study for progressive MS targeting microglia and macrophages.
  • Cladribine.
  • Stem cell transplant for highly active MS.

🔍 Did You Know?

The discovery that chronic active “smouldering” plaques with paramagnetic rims (iron rim plaques) can be visualized on susceptibility-weighted MRI has transformed our understanding of progressive MS. These rim lesions correspond histopathologically to the chronic active plaque with iron-laden macrophages and microglia at the expanding edge. Patients with multiple rim lesions tend to have more disability progression and lower response to standard DMTs. The discovery has practical implications: it provides an MRI biomarker for the “smouldering” process that traditional MS imaging doesn’t capture, allows monitoring of progressive disease activity that previously was invisible, and offers an outcome measure for trials of treatments targeting the chronic inflammation of progressive MS. The recognition has also shifted the conceptual framework: MS is not just a disease of relapses (the focal plaques visible on conventional MRI) but also a chronic smouldering disease (the rim lesions and diffuse white matter damage) that progresses independently of relapse activity. The new BTK inhibitors (tolebrutinib, fenebrutinib) target the microglia and macrophages thought to drive the chronic active plaque — potentially providing the first effective therapy for the smouldering disease that remains MS’s most challenging clinical problem. The lesson: when looking at MRI in MS, attend not only to enhancing acute plaques but also to the chronic active plaques with iron rims — they tell a different story about disease activity.

Pitfalls and Pearls

  • MS plaque: sharply demarcated demyelination; periventricular, corpus callosum, optic, brainstem, cord.
  • Dawson’s fingers: periventricular plaques perpendicular to ventricles.
  • Acute active plaque: foamy macrophages with myelin debris + perivascular lymphocytes.
  • Chronic active (smouldering) plaque: hot rim of macrophages + iron rim sign on SWI.
  • Chronic inactive plaque: cleared center, gliosis, axonal loss; shadow plaques = partial remyelination.
  • Cortical plaques (subpial especially): often missed on conventional MRI; cognitive correlate.
  • Lucchinetti patterns: I (macrophage), II (antibody/complement — plasmapheresis-responsive), III (oligodendrocyte apoptosis), IV (oligodendrocyte degeneration).
  • RRMS → SPMS: most patients transition over 10-20 years.
  • PPMS: progressive from onset, spinal cord predominance; ocrelizumab approved.
  • Tumefactive MS: open ring enhancement, restricted diffusion at rim, distinguishes from tumor.
  • Marburg MS: fulminant; rare.
  • Baló concentric sclerosis: tree-ring appearance.
  • Oligoclonal bands: CSF not serum; supports MS.
  • 2024 McDonald criteria: updated; broader MRI-based dissemination definitions.
  • NMO and MOGAD must be excluded with AQP4-IgG and MOG-IgG testing.
  • BTK inhibitors: emerging therapy targeting chronic active plaque biology.

References

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  3. Lassmann H. Multiple sclerosis pathology. Cold Spring Harb Perspect Med. 2018;8(3):a028936.
  4. Absinta M, Sati P, Reich DS. Advanced MRI and staging of multiple sclerosis lesions. Nat Rev Neurol. 2016;12(6):358-368.
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