Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients

Axonal degeneration has been proposed as a cause of irreversible neurological disability in multiple sclerosis (MS) patients. The purpose of this study was to quantify axonal loss in spinal cord lesions from 5 paralyzed (Expanded Disability Status Scale score > or =7.5) MS patients and to determine if axonal number or volume correlated with levels of the neuronal marker N-acetyl aspartate (NAA). Axonal loss in MS lesions ranged from 45 to 84% and averaged 68%. NAA levels were significantly reduced (>50%) in cross sections of spinal cords containing MS lesions. Reduced NAA correlated with reduced axonal numbers within lesion areas. In addition, NAA levels per axonal volume were significantly reduced in demyelinated axons (42%) and in myelinated axons in normal-appearing white matter (30%). The data support axonal loss as a major cause of irreversible neurological disability in paralyzed MS patients and indicate that reduced NAA as measured by magnetic resonance spectroscopy can reflect axonal loss and reduced NAA levels in demyelinated and myelinated axons.     

Subpial demyelination in the cerebral cortex of multiple sclerosis patients

The extent and pattern of demyelination in the cerebral cortex was determined in 78 tissue blocks from the brains of 20 multiple sclerosis (MS) patients and 28 tissue blocks from 7 patients without neurological disease. Tissue blocks from 4 predetermined areas (cingulate gyrus, frontal, parietal, and temporal lobe) were studied, irrespective of macroscopically evident MS plaques. All tissue blocks contained cerebral cortex and periventricular and/or subcortical white matter. One hundred and nine demyelinating lesions were detected in the cerebral cortex, of which 92 (84.4%) were purely intracortical and 17 (15.6%) were lesions extending through both white and gray matter areas. In 5 of the 20 MS brains, subpial demyelination was extensive in the 4 widely spaced cortical areas studied, thus considered to represent a general cortical subpial demyelination. The percentage of demyelinated area was significantly higher in the cerebral cortex (mean 26.5%, median 14.1%) than in white matter (mean 6.5%, median 0%) (p = 0.001). Both gray and white matter demyelination was more prominent in the cingulate gyrus than in the other areas examined (p < 0.05). These results indicate that the cerebral cortex is likely to be a predilection site for MS lesions and identify general cortical subpial demyelination as a distinct pattern occurring in a significant subpopulation of MS patients.     

Water diffusion is elevated in widespread regions of normal-appearing white matter in multiple sclerosis and correlates with diffusion in focal lesions.

Pathological changes in the normal-appearing white matter in multiple sclerosis are well recognised, but their relationship to pathology in focal lesions is not well understood. Magnetic resonance diffusion imaging is sensitive to abnormalities in the integrity, size and geometry of water spaces in brain tissue. This study investigated the anatomical distribution of normal-appearing white matter diffusion abnormalities and their relationship to diffusion in focal lesions in multiple sclerosis (MS). The average apparent diffusion coefficient (ADCav) was measured by three-axis echoplanar diffusion imaging in normal-appearing white matter regions and lesions throughout the brain in 40 patients, and in white matter in 14 matched controls. The correlation between the ADCav in normal-appearing white matter and lesions was determined. In controls and patients, diffusion was highest in the corpus callosum. Patients had a higher mean ADCav than controls in widespread regions including the corpus callosum, cerebellar, temporal and occipital normal-appearing white matter. Mean normal-appearing white matter ADCav correlated strongly with mean lesion ADCav (r = 0.67, P < 0.001). This study demonstrates that water diffusion is elevated in widespread areas of normal-appearing white matter in MS, and is correlated with diffusion in lesions. These findings suggest that the pathogenetic mechanisms causing tissue damage in lesions and normal-appearing white matter are at least partly linked.     

Balo's concentric demyelination diagnosed premortem

We report the first antemortem diagnosis of a lesion showing Balo's concentric sclerosis. A patient with a progressive left hemiparesis had a ring-enhancing, low-density right frontal white matter lesion. On myelin stains of a needle biopsy, alternating demyelinated and myelinated zones in the white matter were diagnostic of concentric sclerosis. The patient improved with prednisone therapy, but relapsed temporarily 15 months later. CT and MRI showed additional lesions, but no features unique to this process. He remains alive and employed 3 years after diagnosis.     

Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration

The present study examined the extent and distribution of lymphocyte infiltration in demyelinated lesions in the cerebral cortex of multiple sclerosis (MS) patients. Tissue sections from the brain of 10 MS patients and five patients without neurological disease were double labeled for myelin basic protein and the lymphocyte markers CD3, CD4, CD8, CD45RO, and CD20. The highest density of CD3-positive T cells was found in MS white matter lesions (40.4/10 high power fields (hpf)). Fewer T cells were detected in cortical lesions that extended through both white and gray matter (12.1/10 hpf; P < 0.001). The lowest number of T cells was detected in intracortical demyelinated lesions (1.1/10 hpf). This was equal to the lymphocyte density in nondemyelinated cerebral cortex within the same tissue block (1.1/10 hpf) or cerebral cortex in control brains (1.8/10 hpf). A similar distribution was found using the CD4, CD8, and CD45RO markers. CD20-positive B cells were scarce in all specimens examined. These data indicate that areas of intracortical demyelination in chronic MS are not associated with an increased number of lymphocytes, or an altered distribution of lymphocyte subsets, when compared with control areas in MS and control patients. This finding indicates that the extent of lymphocyte infiltration in MS lesions is dependent on lesion location.     

Formalin fixed brains are useful for magnetic resonance imaging (MRI) study

We carried out magnetic resonance imaging (MRI) studies on human brains which had been fixed in formalin solution for over 2 years and had been proven neuropathologically to be cases of multiple sclerosis (MS), progressive multifocal leukoencephalopathy (PML), and Balo's concentric sclerosis (Balo). Using spin echo (SE) and inversion recovery (IR) pulse sequences to detect demyelinated lesions in a living person with MS, the demyelinated lesions of the fixed brains in cases of MS, PML and Balo definitely re-appeared, although T1 and T2 in the gray and white matter were reduced following fixation. High signal areas on the SE images corresponded not only to the characteristic distribution of demyelinated lesions in the white matter but also to sparse myelin, gliosis and mild perivascular cuffing in the white matter around the demyelinated foci in cases of the fixed MS, PML and Balo brains. On the IR images, only MS plaques were evident. This MRI study of fixed brains proved useful to elucidate clinicopathological correlations.     

Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that causes motor, sensory, and cognitive deficits. The present study characterized demyelinated lesions in the cerebral cortex of MS patients. One hundred twelve cortical lesions were identified in 110 tissue blocks from 50 MS patients. Three patterns of cortical demyelination were identified: Type I lesions were contiguous with subcortical white matter lesions; Type II lesions were small, confined to the cortex, and often perivascular; Type III lesions extended from the pial surface to cortical layer 3 or 4. Inflammation and neuronal pathology were studied in tissue from 8 and 7 patients, respectively. Compared to white matter lesions, cortical lesions contained 13 times fewer CD3-positive lymphocytes (195 vs 2,596/mm3 of tissue) and 6 times fewer CD68-positive microglia/macrophages (11,948 vs 67,956/mm3 of tissue). Transected neurites (both axons and dendrites) occurred at a density of 4,119/mm3 in active cortical lesions, 1,107/mm3 in chronic active cortical lesions, 25/mm3 in chronic inactive cortical lesions, 8/mm3 in myelinated MS cortex, and 1/mm3 in control cortex. In active and chronic active cortical lesions, activated microglia closely apposed and ensheathed apical dendrites, neurites, and neuronal perikarya. In addition, apoptotic neurons were increased significantly in demyelinated cortex compared to myelinated cortex. These data support the hypothesis that demyelination, axonal transection, dendritic transection, and apoptotic loss of neurons in the cerebral cortex contribute to neurological dysfunction in MS patients.     

Baló's concentric sclerosis: surviving normal myelin in a patient with a relapsing-remitting dinical course.

Baló's concentric sclerosis is a demyelinating disorder in which bands of demyelination alternate with concentric bands of myelin preservation. The pathogenesis of the lesion is unknown. Previous reports using modern histopathologic techniques have shown the bands of myelin preservation to be comprised of remyelinated or partially demyelinated myelin. Here we report a case of Baló's concentric sclerosis in a 24-year-old East Indian patient with a previous history of relapsing-remitting multiple sclerosis (MS). Pathologically, the bands of myelin preservation showed myelin sheaths of normal thickness, with focal areas of demyelination. The findings, taken together with those of previously reported cases, suggest that Baló's concentric sclerosis is a variant of MS, and the concentric lesion may be an intermediary form in evolution of a chronic active MS plaque. The pathogenesis of this concentric lesion may be explained by periodic suppression of demyelination in the rapidly expanding border, allowing remyelination or only transient incomplete demyelination to occur.     

Aquaporin-4 astrocytopathy in Baló’s disease

Baló’s concentric sclerosis (BCS) is considered to be a rare variant of multiple sclerosis and characterized by alternating rings of demyelinated and preserved myelin layers. The mechanism underlying BCS remains to be elucidated. Recently, occurrence of concentric rings of Baló was described in the brainstem of a patient with neuromyelitis optica (NMO). Because selective loss of aquaporin-4 (AQP4) and vasculocentric deposition of complement and immunoglobulins are characteristic in NMO, we aimed to assess AQP4 expression in the concentric demyelinating lesions of BCS patients. We evaluated AQP4 expression relative to expression of another astrocytic marker (glial fibrillary acidic protein), the extent of demyelination, lesion staging and perivascular deposition of complement and immunoglobulin in four cases with BCS, and 30 individuals with other neurological diseases. All cases with BCS demonstrated extensive AQP4 loss in both demyelinated and myelinated layers of all actively demyelinating lesions, with perivascular lymphocytic cuffing of T cells, but no deposition of immunoglobulins or complement around vessels. These findings suggest that AQP4 loss occurs in heterogeneous demyelinating conditions, namely NMO and BCS. Furthermore, acute BCS lesions are characterized by extensive AQP4 loss without vasculocentric deposition of complement or immunoglobulin.     

Astrocytopathy in Balo's disease

Baló's disease is characterized by alternating rings of demyelination and preserved myelin. As additional multiple sclerosis (MS)-like lesions often coexist in Baló's cases, Baló's disease is regarded as a variant of MS. In demyelinated areas, many hypertrophic astrocytes are present in close contact with oligodendrocytes, which often show apoptotic features. In the outermost layer of preserved myelin, stress proteins involved in tissue preconditioning are abundant in oligodendrocytes. The peri-plaque perimeter is thus assumed resistant to subsequent attack, thereby leaving a layer of preserved myelin. In some cases, Baló's concentric rings develop step by step in a centrifugal direction, whereas many other cases show simultaneous enhancement of multiple rings. Therefore tissue preconditioning and successive ring formation does not fully describe the mechanism of the disease. We recently reported that in four Filipino Baló's patients, aquaporin-4 (AQP4) was extensively lost in glial fibrillary acidic protein-positive hypertrophic astrocytes, both in demyelinated and myelinated layers of all actively demyelinating lesions. None of six further patients with MRI-confirmed Baló's disease were seropositive for anti-AQP4 antibody. I propose that AQP4 astrocytopathy, in the absence of anti-AQP4 antibody, is characteristic of Baló's disease. This hypothesis should be tested in future experimental studies.     

Human mesenchymal stem cells infiltrate the spinal cord, reduce demyelination, and localize to white matter lesions in experimental autoimmune encephalomyelitis

Mesenchymal stem cells (MSCs) can abrogate the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), but whether this therapeutic effect occurs entirely through systemic immune modulation and whether CNS infiltration occurs after peripheral delivery are uncertain. We studied the clinical and neuropathologic effects of intravenously administered human MSCs (hMSCs) in C57BL/6 mice with EAE. Human MSCs significantly reduced the clinical disease severity, particularly in later disease. Large numbers of hMSCs migrated into gray and white matter at all levels of the spinal cord in both naive mice and mice with EAE. In the latter, hMSCs accumulated over time in demyelinated areas. There were 2 distinct morphological appearances of the hMSCs in the tissue, that is, rounded and less numerous process-bearing forms; very few expressed neural markers. The number of spinal cord white matter lesions and areas of white matter demyelination were reduced after hMSC treatment compared with control treatment. These findings show that central nervous system infiltration occurs after peripheral delivery of hMSCs, that they accumulate where there is myelin damage, and that they are associated with a reduced extent of demyelination. These data support a potential role for hMSCs in autologous cell therapy in multiple sclerosis.     

Disappearance of beta2-adrenergic receptors on astrocytes in canine distemper encephalitis: possible implications for the pathogenesis of multiple sclerosis

It has been reported that astrocytes in the white matter of patients with multiple sclerosis (MS) lack beta2-adrenergic receptors. This abnormality might explain why astrocytes in active MS plaques aberrantly express major histocompatibility (MHC) class II molecules, which play an important role in the immunological cascade leading to myelin destruction. Canine distemper (CD) virus primarily infects astrocytes and causes a demyelinating disease in dogs that closely resembles MS. In control dogs, including three dogs with another inflammatory disease, beta2-adrenergic receptor immunoreactivity was observed on both neurons and astrocytes. In dogs with CD encephalitis, beta2-adrenergic receptors were present on neurons, but were absent on astrocytes in acute lesions, demyelinated lesions, and normal-appearing white matter. Similar to MS, several astrocytes in demyelinated lesions expressed MHC class II. These findings suggest that MS and the demyelinating stages of CD encephalitis have a common pathogenetic factor, and that the loss of astrocytic beta2-adrenergic receptors in MS might be induced by a viral infection of astrocytes.     

Balo同心圆性硬化磁共振成像与弥散加权成像特点及其机制

目的 总结同心圆硬化的MRl及弥散加权成像(DWI)特点,并探讨其影像学变化与可能发生机制的相关性.方法 总结临床确诊的同心圆硬化患者3例,均行头颅MRI及DWI检查,其中1例患者行氢质子波谱成像(1H-MRS).结果 3例患者均为多发病灶,病灶多位于中央白质区,均可见特征性的"同心圆样"或"洋葱皮样"改变,增强扫描旱环形或半环形强化.DWI见病灶呈高、低交替环形信号,表观扩散系数(ADC)值随同心圆病理的脱髓鞘区与髓鞘保留区相问存在而出现高低相间变化.结论 Balo同心圆硬化MRI和DWI表现具有特征性,可与病理改变对应,为加深该病发生机制认识提供影像学证据.     

多发性硬化周围神经损伤的病理与临床分析

目的：报道12例多发性硬化（MS）患者周围神经病理检查的异常改变，从中证实MS患者存在周围神经的节段性脱髓鞘病损。方法：12例经肌电图检查发现存在周围神经异常改变的患者行腓肠神经活检及病理学观察。结果：11例标本形态上以脱髓鞘为主，8例可见有髓纤维减少，电镜下显示髓鞘失，有髓纤维再生，形成空泡；神经膜细胞增殖生形成葱头改变；7例可见髓鞘板层松解现象，结论：MS患者不但出现CNS的脱髓鞘病理，而且部分患者同时存在周围神经系统的脱髓鞘病损。     

Remyelinated lesions in multiple sclerosis: magnetic resonance image appearance

BACKGROUND: Various types of pathologic mechanisms in multiple sclerosis (MS) can alter magnetic resonance imaging (MRI) signals, and the appearance of remyelinated lesions on MRI is largely unknown. OBJECTIVE: To describe the MRI appearance of remyelinated lesions in MS. DESIGN: Comparison of postmortem MRI findings with histopathologic findings. SETTING: Brain donations from a general community.Patients Magnetic resonance images from 36 rapid autopsies yielded 161 areas that could be matched with histologic characteristics, including 149 focal T2-weighted abnormalities, with a range of signal intensities on T1-weighted images. In a subset of 49 lesions, magnetization transfer ratio could be determined. MAIN OUTCOME MEASURES: An observer blinded to the MRI findings assessed the presence of remyelination using light microscopic criteria; in 25 areas, in situ hybridization was used to assess the presence of oligodendrocytes expressing proteolipid protein messenger RNA. RESULTS: Remyelinated areas were found in 67 lesions (42%): partial remyelination was present in 30 lesions (19%), whereas 37 lesions (23%) were fully remyelinated. Remyelinated lesions contained enhanced numbers of oligodendrocytes containing proteolipid protein messenger RNA. All areas with remyelination shown histopathologically were hyperintense on T2-weighted images. Strong hypointensity on T1-weighted images was significantly associated (chi2 = 29.8, P<.001) with demyelinated and partially remyelinated lesions compared with fully remyelinated lesions. The magnetization transfer ratio of remyelinated lesions (mean [SD], 27.6% [41%]) differed (F = 46.3, P<.001) from both normal-appearing white matter (35.2% [32%]) and demyelinated lesions (22.3% [48%]). CONCLUSIONS: Remyelinated lesions return an abnormal signal on T2-weighted images. Both T1-weighted images and magnetization transfer ratio may have (limited) additional value in separating lesions with and without remyelination.     

Grey matter pathology in multiple sclerosis

Although multiple sclerosis (MS) has been considered a white matter disease, MS lesions are known to occur in grey matter. Recent immunohistochemical studies have demonstrated extensive grey matter demyelination in chronic MS. The most common lesion type consists of purely cortical lesions extending inward from the surface of the brain, this lesion subgroup is grossly underestimated by standard histochemical myelin staining methods. Some MS patients have subpial demyelination in all cortical areas of the brain; this pattern has been termed 'general cortical subpial demyelination'. Extensive cortical demyelination is associated with the progressive phases of disease, as less cortical demyelination has been detected in relapsing-remitting MS. The pathology of grey matter lesions differs from that of white matter lesions; grey matter lesions are less inflammatory, with less macrophage and lymphocyte infiltration. In purely cortical lesions there is no significant increase in lymphocytes compared with non-demyelinated adjacent cortical areas in MS patients or cerebral cortex in control patients. Significant axonal transection and neuronal loss have been demonstrated in grey matter MS lesions. Current magnetic resonance imaging (MRI) methods are not sensitive for purely cortical MS lesions. The clinical significance of cortical MS lesions may not be characterised until more sensitive MRI methods are developed.     

Cranial CT appearance of acute multiple sclerosis

In acute multiple sclerosis, cranial computerized tomography (CT) may show periventricular and deep white matter contrast-enhanced lesions that are easier to see using 8 mm rather than 13 mm cranial CT sections. Follow-up studies show that the lesions evolve either to areas of density similar to the surrounding white matter or to low-density lesions. We presume they represent foci of active demyelination with extravasation of iodine through an altered blood-brain barrier. Enhanced cranial CT studies may be helpful in diagnosing acute multiple sclerosis and in following the course of the white matter lesions.     

Measurement of low-molecular-weight antioxidants, uric acid, tyrosine and tryptophan in plaques and white matter from patients with multiple sclerosis.

The levels of the antioxidants ascorbic acid, cysteine, reduced glutathione and alpha-tocopherol, of the free-radical marker uric acid and of the amino acids tyrosine and tryptophan were measured by means of high-pressure liquid chromatography in plaques, adjacent white matter and distant white matter from patients with multiple sclerosis, and in central nervous system tissue from patients without neurological diseases. Cholesterol and DNA were also determined, to check demyelination and cellularity. Uric acid was increased and glutathione correspondingly decreased in plaques; alpha-tocopherol was lowest in plaques and highest in distant white matter in all cases. Ascorbic acid, cysteine, tyrosine and tryptophan were not significantly changed in any tissue. The results provide evidence supporting the involvement of free radicals in multiple sclerosis.     

Laminar scars in cerebral white matter: a perinatal injury due to edema

Branched plate-like demyelinated lesions were present in the gyral and central white matter of two individuals, 3 and 54 years of age. The degenerated areas contained very few axons and were densely gliotic, and in the older case, contained connective tissue fibers and were continuous with a large parenchymal cyst. The lesions were covered on both sides by normally myelinated white matter, often representing only the subcortical arcuate white matter, occasionally being considerably broader. In some of the latter zones, there was a central area of less severe degeneration which, however, spared the arcuate zone which remained normal. It is suggested that these lesions represent the effects of edema induced by birth injury, under circumstances which permitted the continued formation and maturation of white matter after the edema had subsided. The edema is thought due for the most part to diffuse hypoxia and acidosis, but other mechanisms, such as infection, venous stasis and trauma, may have contributed to the pathogenesis of the edema, and to the lesions directly.     

Quantitative contrast-enhanced magnetic resonance imaging to evaluate blood-brain barrier integrity in multiple sclerosis: a preliminary study.

Gadolinium enhanced magnetic resonance imaging detects focal blood-brain barrier breakdown in new inflammatory multiple sclerosis lesions, but such lesions do not correlate with disease progression. To explore whether the latter might relate to subtle but widespread blood-brain barrier (BBB) breakdown with low grade inflammation mediating tissue damage, quantitative techniques were used to detect subtle gadolinium enhancement within otherwise normal-appearing white matter and within lesions not showing visible enhancement. T1-weighted imaging was performed prior to and at 5, 20 and 40 min following injection of 0.3 mmol/kg gadopentate dimeglumine in 33 patients with multiple sclerosis and five healthy control subjects. In healthy controls, a significant increase in white matter signal 5 min following contrast injection was observed (1.8%, P < 0.0005); the signal returned to baseline values by 20 min. In multiple sclerosis patients, a non-significant trend was noted for signal to remain elevated in normal-appearing white matter at the 20 and 40 min post-contrast time points; this was most apparent in primary progressive multiple sclerosis. Significant increases in signal intensity were noted at all time points post contrast in apparent non-enhancing lesions. The transient post contrast signal increase in controls is likely due to intravascular gadopentate dimeglumine. The persistent increases in signal intensity in non-enhancing lesions suggest more widespread abnormalities in BBB than is visually apparent, but substantiation of BBB leakage in normal appearing white matter will require further study using more sensitive methods.