Biomedical Scientist, doctorate in Bioengineering. Determined to contribute to a world in which Healthcare and Innovation are accessible to everyone.
Multiple sclerosis (MS) is a chronic neuroinflammatory disease that affects the brain and spinal cord, especially in women, and has an average age of onset of 30 years. MS patients experience a progressive neurological decline that can lead to visual disturbances, fatigue, pain, cognitive deficits, and motor impairment.1
An MS diagnosis is made using a combination of clinical examination of the signs and symptoms, laboratory tests, and radiographic findings such as magnetic resonance imaging (MRI).2 MRI coupled with laboratory tests are important not only for establishing the diagnosis but also for following the course of the disease. These imaging studies focus on evaluating the presence and distribution of lesions in the central nervous system (CNS).3
Pathological Mechanisms in MS
The pathophysiology of MS is limited to the primary CNS, where 2 processes occur. The first is focal inflammation that leads to the formation of macroscopic plaques and injury to the blood-brain barrier. The second is neurodegeneration with microscopic injury, which affects different components of the CNS such as axons, neurons, and synapses. Inflammation, demyelination, gliosis, and neuronal loss can take a relapsing-remitting or progressive course. Patients may have chronic disease that is stable or progressive disease that rapidly worsens. The lesions caused by the disease can be disseminated in time and space meaning that they can occur at different time points and in different locations. The distribution of the lesions is correlated with the variety of clinical manifestations.4
The infiltration of cells in the white and grey matters of the brain, brainstem, spinal cord, and optic nerves leads to inflammation, demyelination, and axonal degeneration.1,5 Inflammation induces tissue damage while pro-inflammatory cells in the CNS overexpress soluble factors that lead to demyelination. Inflammation is present in the lesions in all stages of MS disease, however more inflammation is noticed in more advanced lesion stages.6
Lesions in MS
Even though there is no established histological classification of MS lesions, these can be histologically distinguished in the different phases of the disease and can also show differences in the demyelination degree within the same stage.7,8
MS lesions can be designated as active, inactive, or mixed active/inactive.6,7 This differentiation is based on the presence of inflammatory cells and the existence of demyelination.7 Histological and immunohistological stains can be used for identifying these lesions and observing the presence/absence of myelin (luxol fast blue-Periodic acid-Schiff or immunohistochemistry with antibodies against myelin basic-protein or proteolipid-protein) or to observe the typical tissue and cellular morphology (hematoxylin and eosin stains).7,8 Specific markers for macrophages (CD68) or stains for axons, astrocytes, and specific lymphocytes may be also used during the histological observation.8
Active lesions may be classical, developing in patients with acute MS or relapsing-remitting MS (RRMS), or can be slowly expanding lesions in progressive MS.6 Macrophages are found distributed along with these active lesions.6,7 Lymphocytes, particularly CD8-positive cytotoxic T cells, and plump-shaped and mitotic astrocytes are also present. There are variable degrees of oligodendrocyte injury. Cells are activated, leading to tissue damage and demyelination; although this activation is mostly observed in the edge of the lesion, it can also be present in the periplaque and in the white matter.6 Typically, the center of these active lesions does not show microglial cells, and when it does, these are macrophages where portions of degraded myelin sheaths may be observed and further used for staging the lesion.9
Inactive lesions are the most common and frequent lesions in MS.6 In these lesions, there is demyelination and reactive gliosis, but no macrophages are found while axons are preserved to some extent.6,7 A scar of fibrillar tissue forms between the demyelinated axons, and the center of the plaque shows a highly reduced cell number.6 Perivascular inflammation is relatively decreased compared to active plaques. There is also resolving edema and the appearance of oligodendrocyte precursor cells.
Mixed active/inactive lesions are characterized by the deposition of macrophages in the border of the plaque. Hypertrophic astrocytes may also be found. These lesions show demyelination, either ongoing or that has previously occurred.7 They are not commonly seen in patients with a short time of disease, but in patients diagnosed with MS for more than 10 years.10
Demyelination Patterns in MS
Histological studies show the existence of 4 patterns of demyelination in MS.11,12 Patterns I and II have many features in common, where demyelination results from an important inflammation process.12 The main difference between pattern I and pattern II is that only in pattern II prominent deposition of Igs and complement C9neo antigen were observed at sites of active myelin destruction.12
In pattern III, no deposition of Ig or complement is observed. The borders of active lesions showing a type III pattern are ill-defined and a portion of myelin can be seen surrounding the inflamed vessels within the plaque. This pattern presents oligodendrogliopathy, with reduced oligodendrocytes in the border of the active plaque.12 Nuclear condensation and fragmentation are present.7 Dysregulation of myelin proteins is observed.7,12
Pattern IV is uncommon.7,8 It is characterized by the degeneration of oligodendrocytes with a low ability of repair in the center of the lesion. Demyelination results from oligodendrocyte death.12
Remyelination can be observed when the disease is in its early stages.13 This axon remyelination occurs due to the presence of new oligodendrocytes.6 Remyelinated shadow plaques are easily distinguished from the surrounding tissue as their borders are sharp and identifiable as discolored areas of myelin loss.13 Either the majority or only portions of the lesions may be remyelinated.7 As MS progresses, it becomes more difficult for oligodendrocytes to continue replacing myelin.11
1. Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015;15(9):545-558. doi:10.1038/nri3871
2. McGinley MP, Goldschmidt CH, Rae-Grant AD. Diagnosis and treatment of multiple sclerosis: a review [published correction appears in JAMA. 2021;325(21):2211]. JAMA. 2021;325(8):765-779. doi:10.1001/jama.2020.26858
3 Brisset JC, Vukusic S, Cotton F. Update on brain MRI for the diagnosis and follow-up of MS patients. Presse Med. 2021;50(2):104067. doi: 10.1016/j.lpm.2021.104067
4.Tafti D, Ehsan M, Xixis KL. Multiple sclerosis. In: StatPearls [Internet]. StatPearls Publishing; 2021. Accessed June 28, 2021.
5. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372(9648):1502-1517. doi:10.1016/S0140-6736(08)61620-7
6. Lassmann H. Multiple sclerosis pathology. Cold Spring Harb Perspect Med. 2018;8(3):a028936. doi:10.1101/cshperspect.a028936
7. Kuhlmann T, Ludwin S, Prat A, et al. An updated histological classification system for multiple sclerosis lesions. Acta Neuropathol. 2017;133(1):13-24. doi:10.1007/s00401-016-1653-y
8. Popescu BF, Pirko I, Lucchinetti CF. Pathology of multiple sclerosis: where do we stand? Continuum (Minneap Minn). 2013;19(4 Multiple Sclerosis):901-921. doi:10.1212/01.CON.0000433291.23091.65
9. Brück W, Porada P, Poser S, et al. Monocyte/macrophage differentiation in early multiple sclerosis lesions. Ann Neurol. 1995;38(5):788-796. doi:10.1002/ana.410380514
10. Frischer J, Weigand S, Guo Y, et al. Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque. Ann Neurol. 2015;78(5):710-721. doi:10.1002/ana.24497
11. Jarius S, König F, Metz I, et al. Pattern II and pattern III MS are entities distinct from pattern I MS: evidence from cerebrospinal fluid analysis. J Neuroinflammation. 2017;14(171). doi:10.1186/s12974-017-0929-z
12. Lucchinetti C, Brück W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H, et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol. 2000;47(6):707-717. doi:10.1002/1531-8249(200006)47:6<707::aid-ana3>3.0.co;2-q13. Chari DM. Remyelination in multiple sclerosis.Int Rev Neurobiol. 2007;79:589-620. doi:10.1016/S0074-7742(07)79026-8
Reviewed by Ioannis Nikitidis, PhD, on 7/1/2021.
Reviewed by Ioannis Nikitidis, PhD, on 7/1/2021.