Clinicopathological Features of Inflammatory Demyelinating Diseases in Biopsy
Inflammatory demyelinating diseases (IDD) of the central nervous system (CNS) are a group of disorders that lead to significant neurological disability, particularly in young adults. These diseases are characterized by inflammation and damage to the myelin sheath, which is essential for the proper functioning of nerve cells. Early diagnosis of IDD is crucial as it allows for prompt immunotherapy, which can minimize relapse, disability, and mortality. Multiple sclerosis (MS) is the most common IDD in adults, and while the histological characteristics of chronic MS lesions are well-known, diagnosing an inflammatory demyelinating process in biopsy specimens can be challenging. This is due to the small size of the specimens and the fact that they often represent only a part of a larger lesion. Additionally, the histopathological features of acute MS differ significantly from those of chronic demyelinated plaques observed in autopsies.
The study retrospectively analyzed the clinical and histopathological features of 23 IDD cases diagnosed at the Department of Pathology, Xuanwu Hospital, Capital Medical University, between 2009 and 2017. The researchers used Luxol fast blue (LFB) staining and immunohistochemical (IHC) staining to explore the pathological diagnosis of IDD in biopsy specimens. Five consecutive cases of ischemic infarction diagnosed from 2009 to 2016 were selected as the control group. The study was approved by the ethics committees of Xuanwu Hospital, and informed consent was obtained from all patients. Data analysis was performed using SPSS 19.0, and the Kruskal-Wallis test was used for comparison of the course of the disease among three stage groups, with a P value < 0.05 considered statistically significant.
The study included 23 IDD patients, with 11 males and 12 females. The patients’ age at the time of diagnosis ranged from 10.0 to 68.0 years, with a median age of 37.0 years. These patients were younger than those with ischemic infarction, who had a median age of 50.0 years. Complete medical history data were obtained from 17 of the 23 IDD patients, and the clinical symptoms varied according to the location of lesions. Symptoms included headache and dizziness, limb weakness and movement disorder, limb numbness, nausea and vomiting, blurred vision and vision hemianopia, slurred speech, and mouth angle deviation. The time from the onset of symptoms to biopsy ranged from 7 days to 5 months, with a median of 30 days. One patient developed IDD 11 months after hematopoietic stem cell transplantation, highlighting that IDD is an uncommon but serious complication of allogeneic bone marrow stem cell transplantation.
Magnetic resonance imaging (MRI) showed that nine cases of IDD had a single focus, four cases involved two regions, and four cases involved three or more regions. The IDD lesions involved almost all areas of the CNS, including the frontal lobe, temporal lobe, parietal lobe, insular lobe, periventricular area, basal ganglia, corona radiata and semioval center, cerebellum, and spinal cord. Most of the MRI signals in IDD lesions were long T1 and long T2 with enhancement and were diagnosed as space-occupying lesions, which are difficult to distinguish from tumors; thus, biopsy was performed.
Histopathological analysis using hematoxylin-eosin (H&E) staining revealed that all IDD lesions were hypercellular and characterized by diffuse and dense infiltration of the complete lesion area with foamy macrophages, which were CD68-positive. T cell-dominated lymphocytes were localized around small blood vessels and scattered between foam cells. Reactive astrocytes proliferated in all lesions and became plump-shaped (gemistocytes) with homogeneous eosinophilic cytoplasms, and numerous fibrillary processes were shown by glial fibrillary acidic protein (GFAP) staining. Mitotic astrocytes and astrocytes with fragmented nuclear inclusions (granular mitoses and Creutzfeldt-Peters cells) were found in two cases. IHC for neurofilament (NF) showed that axons were relatively preserved, with some axons becoming swollen and forming axonal spheroids.
LFB staining showed myelin sheath loss in all IDD cases studied. IHC staining for proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG) showed the same results, but staining for these proteins was clearer than LFB staining. In some cases, LFB-positive myelin sheath fragments were found in the cytoplasm of macrophages. The PLP staining results were highly consistent with LFB staining and clearly showed degradation products of myelin sheaths in macrophages. However, the staining results of MOG were different from those of LFB and PLP, with MOG-positive granules found in the cytoplasm of macrophages in only 15 cases. This is likely because the degradation of minor myelin proteins (e.g., MOG) occurs rapidly, and the digestion of major myelin proteins (e.g., PLP) is slower.
IDD lesions were classified based on lesion activity. Of the 23 patients examined, 15 exhibited lesions that were classified as active and early demyelinating lesions, six exhibited lesions that were classified as active and late demyelinating lesions, and two exhibited lesions that were classified as active and post-demyelinating lesions. Thus, the lesions in the small biopsies in this study were all active lesions, and no chronic inactive demyelinating lesions, which are commonly observed in autopsy specimens, were found. There was no statistical significance in the time from the appearance of symptoms to biopsy among the three groups, indicating that disease stage did not correspond to the course of the disease; this may have been because biopsy represents only one lesion, while the symptoms result from a combination of multiple lesions, precisely reflecting the spatial multiplicity of IDD lesions.
In the control group, four of the five ischemic cerebral infarction lesions showed demyelination, and PLP- and MOG-positive granules were found in macrophages in two cases. This is because phagocytes also ingested and degraded necrotic myelin fragments after cerebral infarction. However, axons were also necrotic in ischemic cerebral infarction. Therefore, cerebral infarction and IDD can be differentiated by combining clinical manifestations with IHC staining for NF since axons in cerebral infarction lesions are absent while axons in IDD are relatively preserved.
In conclusion, the study demonstrated that to make a pathological diagnosis of IDD in biopsy, the clinical manifestations, MRI, and pathological morphology should be combined for comprehensive analysis. IHC staining of PLP, MOG, NF, CD68, and GFAP is helpful for the pathological diagnosis and staging of IDD in biopsy and can be routinely used in general neuropathological analyses.
doi.org/10.1097/CM9.0000000000000738
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