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Journal of Neurological Disorders and Stroke

Neuropathology of Demyelinating Diseases in Japan

Review Article | Open Access | Volume 2 | Issue 5

  • 1. Institute for Medical Science of Aging, Aichi Medical University, Japan
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Corresponding Authors
Mari Yoshida, Institute for Medical Science of Aging, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi,480-1195 Japan, Tel: 81-0561-62-3311; Fax: 81- 0561-63-3531
ABSTRACT

We reviewed and compared the neuropathology of multiple sclerosis (MS), neuromyelitis optica (NMO), neuromyelitis optica spectrum disorders (NMOSD) and acute disseminated encephalomyelitis (ADEM) in Japan. Demyelinating lesions of MS are well circumscribed as compared with the lesions of NMO and NMOSD, which reveal variable, irregularly shaped and ill-defined borders that extend longitudinally along vessels, causing destructive changes with poor gliosis. Although the optic nerves and chiasm, spinal cord, cerebral white matter, brainstem, and cerebellum are involved in both MS and NMO/NMOSDs, the formation patterns of demyelinating lesions appear to differ between MS and NMO/NMOSD. NMO/NMOSD preferentially exhibit central lesions of the spinal cord with strongly softening features. Furthermore, the expression of myelin basic protein (MBP) is strongly diminished in the demyelinating lesions of MS, without loss of aquaporin-4 (AQP4) or GFAP expression. However, AQP4 and GFAP expression is decreased in the demyelinating lesions of NMO/NMOSD. Therefore, AQP4 and MBP immunoreactivity may distinguish NMO/NMOSD from MS neuropathologically. Serial sections of the spinal cord demonstrate longitudinally extensive lesions in NMO/NMOSD, although some cases with MS also reveal similar longitudinally extensive lesions of the spinal cord. In ADEM, demyelinating lesions form primarily in small perivenous foci that differ from the lesions of MS and NMO/NMOSD. Therefore, the shape and formation patterns of demyelinating lesions appear to be disease specific, and it might be possible to distinguish among MS, NMO and ADEM; the immunoreactivity patterns of MBP, AQP4, and GFAP may also aid diagnosis.

CITATION

Yoshida M (2014) Neuropathology of Demyelinating Diseases in Japan. J Neurol Disord Stroke 2(5): 1086.

KEYWORDS

•    Multiple sclerosis
•    Neuromyelitis optica spectrum disorders
•    Acute disseminated encephalomyelitis
•    Myelin basic protein
•    Aquaporin-4

ABBREVIATIONS

ADEM: Acute Disseminated Encephalomyelitis; AHL: Acute Hemorrhagic Leukoencephalopathy; MS: Multiple Sclerosis; NMO: Neuromyelitis Optica; NMOSD: Neuromyelitis Optica Spectrum Disorders; C: Cervical Cord; T: Thoracic Cord; L: Lumbar Cord

INTRODUCTION

The pathology of demyelination is defined as the destruction of normal myelin with relative preservation of axons. The term demyelination excludes diseases characterized by a loss of myelin due to an inherited defect of metabolism (leukodystrophies) or a loss of myelin as a result of axonal degeneration.

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system. NMO, also known as Dévic’s disease, is characterized by the acute development of optic neuritis and acute transverse myelitis within weeks of each other [1-5]. Until relatively recently, NMO has been classified as a subtype of multiple sclerosis. There has long been controversy concerning whether NMO is a variant of MS, called optic-spinal multiple sclerosis (OSMS) in Asian countries, or a distinct disease [1-5]. After the identification of AQP4, which is the main water channel protein in the CNS and is densely expressed on astrocyte endfeet at the blood-brain barrier (BBB), the loss of AQP4 in NMO lesions revealed distinct pathogenesis and pathology, distinguishing it from MS [6,7].

The recognition of variable distributions of NMO lesions in regions other than the spinal cord and optic nerves has promoted the concept of NMO spectrum disorders (NMOSD) [8,9]. We use the term NMOSD as a comprehensive concept in this review. We reviewed the neuropathology of 27 autopsied cases with demyelinating diseases in Japan and demonstrated the characteristic features of MS, NMOSD and ADEM. These patients were chosen from the files of the Institute for Medical Science of Aging, Aichi Medical University, between 1980 and 2013. The demographic features of all of the included cases are summarized in the Table 1. The pathological diagnosis revealed 9 cases with MS, 14 cases with NMOSD, 3 cases with ADEM and 1 case with AHL (Table 1). In cases with NMOSD, 2 cases were combined with Sjögren syndrome. It is interesting that NMOSD cases were more frequent than MS cases in Japan, although this may be biased by the autopsied series. Some cases that were previously diagnosed as MS were reassessed and classified as NMOSD. We present the macroscopic and microscopic features of MS, NMOSD and ADEM and confirm the discriminations of these demyelinating disorders based on their neuropathologies.

Table 1: Table Demographics of NMOSD, MS and ADEM patients.

Case Age (years)/sex Disease duration Pathological diagnosis Pathological lesions
ON Spinal cord (LETM) Distribution of lesions
1 55/F 7 years NMOSD + + (+) ON, spinal cord, cerebral white matter
2 23/M 4 years MS + ON, brainstem, cerebellum, periventricular white matter
3 63/F 5 years NMOSD + NE ON, brainstem, thalamus
4 43/M 8 years NMOSD + + (+) ON, spinal cord, brainstem, cerebellum, cerebral white matter
5 59/M 3 months MS + + (−) ON, spinal cord, cerebral white matter
6 54/F 27 years MS + ± (−) ON, spinal cord, brainstem, cerebral white matter & cortices
7 82/M 6 years NMOSD + + (+) ON, spinal cord
8 64/M 38 days ADEM + + (+) ON, spinal cord, brainstem, cerebral white matter
9 74/F 11 years NMOSD + + (+) ON, spinal cord, brainstem, cerebral white matter
10 46/F 3 years NMOSD + + (+) ON, spinal cord, brainstem, cerebellum, cerebral white matter
11 68/F 2 months MS + + (+) ON, spinal cord, brainstem
12 29/M 14 days AHL + (−) Brainstem, basal ganglia, cerebral white matter
13 74/F 2 months NMOSD + (+) Spinal cord
14 67/F 5 years NMOSD + (+) Spinal cord
15 85/F 11 months NMOSD NE + (+) Spinal cord
16 67/M 5 years MS + + (−) ON, spinal cord, brainstem, basal ganglia
17 68/F 22 years NMOSD + + (+) ON, spinal cord
18 57/M 8 months NMOSD + (+) Spinal cord, brainstem
19 73/F 17 years NMOSD + + (+) ON, spinal cord, cerebral white matter
20 66/M 10 years MS + (−) Spinal cord, cerebral white matter
21 71/F 14 years NMOSD + ON, brainstem, cerebral white matter
22 66/F 4 years MS + + (−) ON, spinal cord, cerebral white matter
23 63/M 5 months ADEM + (+) Spinal cord, brainstem, basal ganglia, thalamus
24 63/M 44 years MS + + (−) ON, spinal cord, cerebral white matter
25 56/M 4 years MS + (−) Spinal cord, brainstem, basal ganglia, thalamus, cerebral white matter & cortices
26 64/F 23 years NMOSD + + (+) ON, spinal cord, brainstem, cerebral white matter
27 60/F 14 days ADEM + (+) Spinal cord, brainstem, basal ganglia, thalamus, cerebral white matter & cortices

f: Female; m: Male; ADEM: Acute Disseminated Encephalomyelitis; MS: Multiple Sclerosis; NMOSD: Neuromyelitis Optica Spectrum Disorder; NE: Not Examined; LETM: Longitudinally Extensive Transverse Myelitis; ON: Optic Neuritis.

MULTIPLE SCLEROSIS

The pathological hallmark of MS is the presence of focal demyelinated plaques with partial axonal preservation and reactive glial scar formation in the white and gray matter of the CNS [10,11]. In addition, there is considerable axonal loss in small nerve fibers [12,13] as well as diffuse damage throughout the normal-appearing white and gray matter [14-17]. With disease progression, these alterations are associated with increasing global brain atrophy.

Macroscopic findings

In fixed tissues, MS plaques in the acute stage appear as well-circumscribed pale regions. When acute stage plaques are large and extending, the spinal cord may show transverse edema and softening (Figure 1). Chronic lesions in the cerebral white matter appear as round well-defined plaques with discoloration (Figure 5A). Cavitated lesions are observed in longstanding severely damaged plaques (Figure 7A).

Microscopic findings

In the acute stage, well-circumscribed demyelination is observed using myelin staining in the optic nerves and chiasm, the cerebral peduncles of the midbrain, the pons, the medullary tegmentum and the spinal cord (Figure 2). Demyelination with marked edema and softening is observed in cases with a rapidly progressive fatal course, known as acute (Marburg-type) MS. Within the plaque, relative preservation of neurons and numerous foamy macrophages and perivascular lymphocytes are observed (Figure 3A,B). Immunohistochemistry for phosphorylated neurofilament indicates relative preservation of axons and loss of staining for MBP (Figures 3,4). The lesions show different stages in time as well as demyelination and remyelination. In inactive lesions, staining for myelin reveals a well-circumscribed, round demyelinating plaque associated with marked hypocellularity, obvious loss of oligodendroglia and gliosis (Figure 5). In contrast to the marked loss of staining for MBP, GFAP and AQP4 immunoreactivity are preserved (Figure 6). In longstanding MS, extensive demyelinating lesions and axonal loss are observed in the subcortical white matter and at the junction between the cerebral cortex and white matter, resulting in global brain atrophy (Figure 7B) [14-17].

Neuromyelitis optica spectrum disorders (MNOSD)

NMO is characterized by the development of optic neuritis and transverse myelitis within weeks of each other [1,3]. Since the identification of AQP4, a diverse spectrum of AQP4-related demyelination has been recognized [6,7,18-24]. In this review, of 14 cases with NMOSD, 8 cases had both optic neuritis and longitudinally extensive transverse myelitis pathologically; two cases had localized lesions only within optic neuritis and transverse myelitis (case 7 and 17); there were 3 cases (cases 13,14 and 18) without optic neuritis; and one case (case 21) without transverse myelitis (Table 1).

Macroscopic findings

In the acute stage, the optic nerves and chiasm and affected regions show swollen edema and softening. In chronic stages of long duration, the macroscopic appearance of spinal cords with a typical NMOSD presentation shows marked and extensive longitudinal atrophy of the cord (Figures 8-10). Cerebral white matter lesions in NMOSDs show multiple irregular cystic lesions in the corpus callosum, temporal white matter and periventricular white matter (Figure 11).

Microscopic findings

In NMOSDs, demyelinating lesions show multiple irregularly shaped areas of softening, which differs substantially from the sharp margin of MS plaques (Figure 12). The transverse sections of the cord show extensive irregular demyelination and longitudinal softening from the cervical cord to the lower thoracic cord, accompanied by Wallerian degeneration in the posterior column and the bilateral pyramidal tract (Figure 12). The irregular lesions on the spinal cord showing cystic destruction extend from the central portion to the adjacent gray and white matter.

The demyelinating lesions of NMOSDs tend to extend along the perivascular region longitudinally (Figure 13A). Axons are more severely decreased in NMOSD lesions than in those of MS (Figure 13B). Foamy macrophages and hyaline thickening of small vessels in the lesion are observed (Figure 13C, D).

AQP4 immunoreactivity is severely decreased in cystic lesions when compared with normal-looking lesions (Figure 14A-C) [18-23]. AQP4 is highly expressed in the astrocytic endfeet around blood vessels. GFAP immunoreactivity is decreased in cystic lesions exhibiting severe damage, whereas GFAP expression remains or may recover in areas showing mild demyelination (Figure 14D-F). Phagocytized corpora amylacea have been reported to be a characteristic feature in acute NMOSD lesions (Figure 15) [25]. The presence of different lesion types is reported to suggest diverse mechanisms of tissue injury in NMO [26].

ACUTE DISSEMINATED ENCEPHALOMYELITIS (ADEM)

ADEM is a multifocal inflammatory disorder of the central nervous system, presenting perivenous encephalomyelitis, postinfectious encephalomyelitis and post-vaccinal encephalomyelitis [27-31]. In the acute phase, swelling of the brainstem, spinal cord or cerebral white matter may be observed in severe cases and may resemble acute MS in some cases (Figure 16). In the chronic stage, small areas of disseminated perivenous demy-elination and perivenous infiltration of lymphocytes and macro-phages are visible microscopically (Figures 17-19). In the spinal cord, transverse sections show multiple irregular foci of demyeli-nation along vessels from the peripheral zone and inflammatory cell infiltration (Figure 20). The formation patterns of demyeli-nating lesions in the spinal cord are characteristic of ADEM and different from those of MS and NMOSDs.

CONCLUSION

Different formation patterns in demyelinating lesions are pathologically evident in MS, NMOSD and ADEM. The characteristic pathological features include well-circumscribed plaques in MS and irregular lesions showing perivascular longitudinal demyelination combined with cystic destructive lesions in NMOSDs (Figure 21). Additionally, the immunoreactivities of MBP and AQP4 differ between MS and NMOSDs, which may aid the pathological reevaluation of past cases diagnosed as MS, OSMS or NMO. These pathological images may contribute to understanding the neuroimaging features of demyelinating diseases. Further investigation is needed to determine the pathomechanism of demyelination.

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Yoshida M (2014) Neuropathology of Demyelinating Diseases in Japan. J Neurol Disord Stroke 2(5): 1086.

Received : 29 Mar 2014
Accepted : 17 Sep 2014
Published : 19 Sep 2014
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