Leukoencephalopathy in HTLV-I-associated myelopathy/tropical spastic paraparesis: MRI analysis and a two year follow-up study after corticosteroid therapy.

Magnetic resonance imaging (MRI) of the brain was studied in 35 patients with HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP), 19 HTLV-I seropositive carriers without HAM/TSP (non-HAM/TSP carriers), 18 patients with HTLV-I seronegative spastic spinal paraparesis (SSP), and 82 HTLV-I seronegative controls with other neurological disorders. The incidence of white matter lesions was significantly higher in HAM/TSP (66%) than in the controls (23%) and SSP (11%). HAM/TSP exceeded non-HAM/TSP carriers significantly in the incidence of multiple white matter lesions (37% vs 10%). HAM/TSP affected the deep and subcortical cerebral white matter multifocally, sparing the periventricular regions. None of the lesions were enhanced by gadolinium-DTPA. HAM/TSP patients with the white matter lesions had both a longer duration of disease and a greater disability than did those without lesions. The white matter lesions gradually increased in number, as the disability status became worse, in spite of the high dose corticosteroid treatment. All these observations suggest that the MRI abnormalities of the HAM/TSP brain may reflect the chronic perivascular inflammation with progressive gliosis (chronic disseminated encephalomyelitis). We propose that brain MRI can be successfully utilized as a reliable and non-invasive measure for following the disease progression in HAM/TSP.     

MRI contributes to the differentiation between MS and HTLV-I associated myelopathy in British Columbian coastal natives

BACKGROUND: Human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in British Columbian Coastal Natives has, to date, been a clinical and laboratory diagnosis. However, magnetic resonance imaging (MRI) abnormalities have been well-described in other populations in which HAM/TSP is endemic. METHODS: In order to assess the usefulness of MRI as a diagnostic tool in this population, we compared scans of HAM/TSP patients with those of HTLV-I positive non-HAM/TSP British Columbian Coastal Natives (carriers) and multiple sclerosis patients presenting with progressive paraparesis. Results: The typical nonspecific findings of thoracic cord atrophy and increased signal in the periventricular and subcortical white matter on T2-weighted images were confirmed in the HAM/TSP patients. Despite a lack of specificity of the MRI findings between HAM/TSP patients and HTLV-I carriers, criteria that could effectively differentiate HAM/TSP patients from multiple sclerosis patients with similar clinical presentations were determined. CONCLUSIONS: Clinical and radiological correlations suggest that longitudinal MRI investigations charting the course of HAM/TSP may reveal the clinical significance of these lesions and further define the role of MRI in the diagnosis of this entity. Magnetic resonance imaging is an important supplement to immunological and clinical data in differentiating multiple sclerosis from HAM/TSP.     

Histopathological analysis of four autopsy cases of HTLV-I-associated myelopathy/tropical spastic paraparesis: inflammatory changes occur simultaneously in the entire central nervous system

Although brain lesions have been described in some cases with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), little is known about the nature of brain lesion and its relation to the spinal cord lesion. In the present study, we performed histopathological analysis of the brain and the spinal cord of four autopsied cases with HAM/TSP to clarify the relationship between the brain and the spinal cord lesions. In two cases with active-chronic inflammation in the spinal cord, perivascular inflammatory infiltration was also seen in the brain, and the composition of cell subsets was similar both in the spinal cord and in the brain. No active inflammatory change was seen in the brain in two cases with inactive-chronic spinal cord lesions. Inflamed vessels were distributed mainly in the deep white matter and in the area between cerebral cortex and white matter of the brain. In the spinal cord inflamed vessels were mainly seen in the bilateral lateral and the ventral posterior columns. Parenchymal infiltration was diffused in the spinal cord but very sparse in the brain, suggesting the importance of parenchymal infiltration in the destruction of tissues. These results suggest that inflammatory changes occurred simultaneously in the spinal cord and in the brain, and that distribution of inflamed vessels closely correlated with the characteristics of vascular architecture of the brain and the spinal cord, which lead to a slow blood flow. This study may help promote a better understanding of the pathogenesis of HAM/TSP. Received: 9 July 1999 / Revised, accepted: 9 November 1999     

Axonal damage revealed by accumulation of beta-amyloid precursor protein in HTLV-I-associated myelopathy

We investigated the localization and extent of beta-amyloid precursor protein (APP) immunoreactivity as a sensitive marker for impairment of fast axonal transport in the spinal cords of patients with HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). The results from this study show that APP, used as a marker of early axonal damage in HAM/TSP lesions, is more intensively expressed in areas of active-inflammatory lesions than those of inactive-chronic lesions. The close localization to the areas containing inflammation (activation of macrophage/microglia) is striking and suggests that axonal damage is closely associated with inflammation in active-chronic lesions. Although inflammatory cell infiltration in the central nervous system (CNS) is rarely found in inactive-chronic lesions, a few clusters of APP+ axons are found in the spinal cord white matter in some cases. The presence of APP+ axons without relation to inflammatory cells in inactive-chronic lesions, suggest that soluble neurotoxic factors might induce axonal changes in the CNS of HAM/TSP. The occasional myelinated fibers in the anterior and posterior spinal roots in lower thoracic to lumbar levels had APP+ axons, suggesting that spinal nerve roots can be affected in HAM/TSP, especially in lower thoracic to lumbar levels. Impairment of fast axonal transport may contribute to the development of disability in patients with HAM/TSP.     

Digitized image analysis reveals diffuse abnormalities in normal-appearing white matter during acute experimental autoimmune encephalomyelitis

Demyelination of the central nervous system is a hallmark of multiple sclerosis and its widely used animal model, experimental autoimmune encephalomyelitis (EAE). Recent studies using magnetic resonance imaging and spectroscopy on multiple sclerosis patients have revealed abnormalities of central nervous system normal-appearing white matter suggesting that micro-demyelination and/ or extensive membrane turnover accompanies and perhaps precedes the appearance of manifest inflammatory lesions. In the present study, we induced EAE in SWXJ mice and analyzed digitized images of immunocytochemically stained spinal cord for detection of myelin proteolipid protein (PLP). We found that digitized image analysis is a highly sensitive, objective methodology for measuring the extent of myelin loss during EAE. Our data show that two-thirds of the measured reduction of myelin PLP occurring in EAE spinal cord could be attributed to a loss of myelin in normal-appearing white matter. The marked decrease in detection of PLP was accompanied by a corresponding decrease in PLP mRNA in the central nervous system. Our results indicate that during acute EAE, diffuse myelin abnormalities extend far beyond visibly detectable inflammatory foci and are characterized by a global decrease in the expression of myelin genes and their encoded proteins. J. Neurosci. Res. 54:364–372, 1998. © 1998 Wiley-Liss, Inc.     

Magnetic resonance imaging of spinal cord lesions in multiple sclerosis.

The clinical and pathological manifestations of multiple sclerosis are due to areas of demyelination which occur throughout the white matter of the central nervous system. MRI of the brain frequently shows abnormalities in the hemispheric subcortical white matter; these are demonstrable in the majority of patients and support the clinical diagnosis of multiple sclerosis. Our studies have shown that while MRI identifies such cerebral lesions in nearly all clinically definite multiple sclerosis patients with illness of duration greater than 10 years, these areas of abnormal T2 signal are present less often in the brains of patients studied within 3 years of disease onset. However, symptoms referable to the long tracts of the spinal cord are prominent in many of these patients. Imaging of the spinal cord has presented technical problems because of the small size of the cord, patient body, heart and respiratory movements, and limitations of surface coil technology. The spinal cord of 77 patients with multiple sclerosis have been imaged, revealing three types of abnormalities: (1) approximately half the cords show regions of abnormal T2 weighted signal; (2) during acute exacerbation, spinal cord enlargement (swelling) may be observed; (3) spinal cord atrophy (narrowing) is found particularly in patients with disease of longer duration and greater disability. Unlike the presence of brain lesions, the existence of spinal cord lesions of high T2 signal is not associated with increasing duration of disease but is correlated with disability status. Of patients with such lesions about one fifth did not exhibit brain lesions discernible by MRI.     

Expression of adhesion molecules and monocyte chemoattractant protein-1 (MCP-1) in the spinal cord lesions in HTLV-I-associated myelopathy

Leukocyte adhesion molecules to endothelium plays an important role in the pathogenesis of inflammatory diseases, including HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). To help define the role of adhesion molecules in HAM/TSP, we studied the expression of lymphocyte function-associated antigen-1 (LFA-1), Mac-1, very late antigen-4 (VLA-4), Sialyl Lewis^x (SLex), intercelluar adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), endothelial leukocyte adhesion molecule-1 (ELAM-1) and monocyte chemoattractant protein-1 (MCP-1) in the spinal cord lesions of HAM/TSP. The results indicate that spinal cord lesions of HAM/TSP have greater VCAM-1 expression on endothelium compared with those of controls. Infiltrating mononuclear cells, especially perivascular lesions, expressed VLA-4. Although the expression of ICAM-1 in the spinal cords was not distinctive between HAM/TSP and controls, infiltrating mononulcear cells in the spinal cords of HAM/TSP strongly expressed LFA-1 and Mac-1. ELAM-1 was expressed on endothelium in the inactive-chronic lesions from three of five HAM/TSP, but was not detectable in the spinal cords of controls. SLex reaction was detectable on occasional perivascular cells in the spinal cord of HAM/TSP, but not in those of controls. MCP-1 was detectable on perivascular infiltrating cells and vascular endothelium in active-chronic lesions. This study suggests that VLA-4/VCAM-1 interaction may play an important role for lymphocyte migration into the central nervous system (CNS), and MCP-1 may also be involved in inflammatory cell recruitment to the CNS in HAM/TSP. Received: 4 September 1995 / Revised, accepted: 23 October 1995     

Neuropathology of human T lymphotropic virus type I-associated myelopathy

In order to clarify pathogenesis of human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) a detailed neuropathological analysis of eight autopsy patients with HAM/TSP was performed. Inflammatory infiltrates of mononuclear cells and degeneration of myelin and axons were noted in the middle to lower thoracic spinal cords and were extended continuously to the entire spinal cord. Horizontal distribution of inflammatory lesions was symmetric at any spinal levels. Immunohistochemical analysis demonstrated T cell dominance. The numbers of CD4+ T cells and CD8+ T cells were present in equal numbers in patients with shorter clinical course. Apoptosis of helper/inducer T cells were observed in the presence of TIA1+ cytotoxic T cells in these active inflammatory lesions. Inflammatory infiltrates were markedly decreased and CD8+/TIA1- T cells were predominated over CD4+ cells in patients with prolonged clinical course. HTLV-I proviral deoxyribonucleic acid (DNA) amounts in the freshly frozen spinal cord measured by quantitative polymerase chain reaction (PCR) were well correlated with the numbers of infiltrated CD4+ cells. In situ PCR of HTLV-I provial DNA using multi-primar pairs demonstrated the presence of HTLV-I infected cells exclusively in the mononuclear infiltrates of perivascular areas. From these findings, it is suggested that the target of the inflammatory process seen in HAM/TSP lesions may be HTLV-I infected CD4+ T cells infiltrating the spinal cord.     

Abnormalities of spinal magnetic resonance images implicate clinical variability in human T-cell lymphotropic virus type I-associated myelopathy

This study investigated the role of human T-cell lymphotropic virus type I HTLV-I infection in 11 patients who developed slowly progressive myelopathy with abnormal spinal cord lesions. The authors performed clinical and neuroradiological examinations and calculated the odds that an HTLV-I-infected individual of a specific genotype, age, and provirus load has HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Anti-HTLV-I antibodies were present in both the serum and cerebrospinal fluid in all of the patients. Abnormal magnetic resonance imaging (MRI) lesions were classified as cervical to thoracic type (CT type), cervical type (C type), and thoracic type (T type). In each type, there was swelling of the spinal cords with high-intensity lesions, which were located mainly in bilateral posterior columns, posterior horns, or lateral columns. Virological and immunological analyses revealed that all patients showed a high risk of developing HAM/TSP. These 11 patients may have developed HAM/TSP, as manifested by spinal cord abnormalities shown on MRI. These MRIs implicate clinical variability of HAM/TSP, which may indicate active-early stages of HAM/TSP lesions.     

Detection of human T-lymphotropic virus type I (HTLV-I) tax RNA in the central nervous system of HTLV-I–associated myelopathy/tropical spastic paraparesis patients by in situ hybridization

Autopsy specimens from 3 patients with human T-lymphotropic virus (HTLV-I)–associated myelopathy/tropical spastic paraparesis (HAM/TSP) were examined for the presence of HTLV-I in the central nervous system (CNS). In situ hybridization using an HTLV-I tax RNA probe detected cells containing HTLV-I RNA in spinal cord and cerebellar sections. HTLV-I infected cells were located within the white matter and, in particular, within the anterior and lateral funiculi of the spinal cord. Consistent with previously described HAM/TSP pathology, there were perivascular infiltrates in these CNS specimens. Significantly, HTLV-I RNA was not localized to these infiltrates but was detected deeper within the neural tissue. Furthermore, phenotypic analysis demonstrated that at least some of the infected cells were astrocytes. While previous polymerase chain reaction studies have demonstrated the presence of proviral HTLV-I in CNS specimens, here we provide evidence for the in situ expression of HTLV-I RNA in the CNS of HAM/TSP patients.     

Activities of daily living and lesion position among multiple sclerosis patients by Bayes network

Magnetic resonance imaging is a highly sensitive approach for diagnosis of multiple sclerosis,and T2-weighted images can reveal lesions in the cerebral white matter,gray matter,and spinal cord.However,the lesions have a poor correlation with measurable clinical disability.In this study,we performed a large-scale epidemiological survey of 238 patients with multiple sclerosis in eleven districts by network member hospitals in Shanghai,China within 1 year.The involved patients were scanned for position and size of lesions by MRI.Results showed that lesions in the cerebrum,spinal cord,or supratentorial position had an impact on the activities of daily living in multiple sclerosis patients,as assessed by the Bayes network.On the other hand,brainstem lesions were very unlikely to influence the activities of daily living,and were not associated with the position of lesion,patient’s gender,and patient’s living place.     

Retrovirus infection and neurological disorders]

Our series of neuropathologic studies on HAM/TSP and AIDS dementia were reviewed. Studies on HAM/ TSP demonstrated chronic inflammatory process in the spinal cord, accentuated inflammation in the area with slow blood flow in the spinal cord, characteristic adhesion molecule expression for T-cell migration, apoptosis of helper T-cells in active inflammatory lesion, correlation of HTLV-I provirus amount with disease activity, and HTLV-I infection and expression of HTLV-I gene on infiltrated T-cells in the spinal cord lesion. Based on these findings, we have proposed a by-stander mechanism as a pathogenesis of HAM/TSP. HIV-1 also involves the CNS, however, its pathogenesis has not been fully studied yet. To understand the pathogenesis of AIDS dementia, we used a SIV-macaque model and demonstrated that there are two independent pathogenic processes in AIDS dementia; AIDS-dependent neuropil degeneration in the cortex caused by T-cell tropic virus, and immune response against invading virus-infected cells in the white matter caused by macrophage tropic virus. The latter mechanism is similar to that of HAM/TSP. Invasion of virus-infected blood cells inside the CNS and a gradual damage of surrounding CNS tissues caused by prolonged immune attack to these virus-infected cells may be a common pathogenic process of retrovirus induced CNS diseases.     

Accumulation of human T-lymphotropic virus type I (HTLV-I)-infected cells in the cerebrospinal fluid during the exacerbation of HTLV-I-associated myelopathy

Human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a slowly progressive, inflammatory disease of the central nervous system (CNS). We report a patient with transverse myelitis, who exhibited acute onset and rapid progression of the disease and whose symptoms resembled those observed in multiple sclerosis with spinal cord presentation. During neurological exacerbation of the condition, the HTLV-I proviral load in the cerebrospinal fluid (CSF) increased to 10 times that in the peripheral blood. This suggests that the accumulation of HTLV-I-infected cells in the CNS contributes to neurological exacerbation. Based on the increased proviral load in the CSF, we diagnosed the disease as acute progressive HAM/TSP. The measurement of the HTLV-I proviral load in the CSF is useful for the diagnosis of HAM/TSP and for monitoring its progression.     

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.     

Anterior periventricular linear lesions in optic-spinal multiple sclerosis: a combined neuroimaging and neuropathological study

There are two distinct subtypes of multiple sclerosis (MS) in Asians, optic-spinal (OSMS) and conventional (CMS). In OSMS, severe spinal cord lesions are characteristic while brain lesions are scant. We sought to clarify atypical brain lesions in OSMS by neuroimaging and pathological studies. For brain MRI, 124 consecutive Japanese patients with clinically definite MS based on Poser criteria were enrolled, 57 with OSMS and 67 with CMS. Ten autopsied cases (seven OSMS and three CMS) were studied pathologically. Although the frequency of brain lesions fulfilling Barkhof criteria was significantly higher in CMS than in OSMS, periventricular linear lesions along with the anterior portion of the corpus callosum and the lateral ventricles were significantly more common in OSMS than in CMS. Pathologically, periventricular lesions in CMS extended deeply into the white matter, while those in OSMS were confined to periventricular areas. T cell infiltration in lesions was prominent in CMS but not in OSMS. Although severe axonal loss and cavity formation were commonly seen in periventricular and spinal cord lesions in OSMS, lymphocytic infiltrates and vessel wall thickening were observed only in the latter. Thus, we suggested that anterior periventricular linear lesions without ovoid ones are characteristic of OSMS.     

Magnetic resonance imaging of Asians with multiple sclerosis was similar to that of the West

Magnetic resonance imaging (MRI) of the brain is the most important paraclinical diagnostic test in multiple sclerosis (MS). The appearance of MRI in Asians with MS is not well defined. We retrospectively surveyed the first brain and spinal cord MRI in patients diagnosed to have MS, according to Poser's criteria in seven regions throughout Asia to define the MRI changes among Asians with MS. There were 101 patients with first brain, and 86 with first spinal cord MRI, 66 of whom had both. The brain MRI showed a mean of 17 lesions per patient in T2 weighted images, mostly asymptomatic. Almost all the lesions were in the white matter, particularly in the juxtacortical, deep and periventricular white matter. A third of the lesions were greater than 5 mm, 14% enhanced with gadolinium. There were more supratentorial than infratentorial lesions at a ratio of 7.5: 1. Ninety five percent of the spinal cord lesions were in cervical and thoracic regions, 34% enhanced with gadolinium. The lesions extended over a mean of 3.6 +/- 3.3 vertebral bodies in length. Fifty (50%) of the brain and 54 (63%) of the spinal MRI patients had the optic-spinal form of MS. The MRI of the optic-spinal and classical groups of patients were similar in appearance and distribution, except that the optic-spinal MS patients have fewer brain but longer and more severe spinal cord lesions. In conclusion, the brain and spinal cord MRI of Asian patients with MS was similar to that of the West, although, in this study, Asian MS patients had larger spinal cord lesions.     

E6020, a synthetic TLR4 agonist,accelerates myelin debris clearance,Schwann cell infiltration,and remyelination in the rat spinal cord

Oligodendrocyte progenitor cells (OPCs) are present throughout the adult brain and spinal cord and can replace oligodendrocytes lost to injury, aging, or disease. Their differentiation, however, is inhibited by myelin debris, making clearance of this debris an important step for cellular repair following demyelination. In models of peripheral nerve injury, TLR4 activation by lipopolysaccharide (LPS) promotes macrophage phagocytosis of debris. Here we tested whether the novel synthetic TLR4 agonist E6020, a Lipid A mimetic, promotes myelin debris clearance and remyelination in spinal cord white matter following lysolecithin‐induced demyelination. In vitro, E6020 induced TLR4‐dependent cytokine expression (TNFα, IL1β, IL‐6) and NF‐κB signaling, albeit at ～10‐fold reduced potency compared to LPS. Microinjection of E6020 into the intact rat spinal cord gray/white matter border induced macrophage activation, OPC proliferation, and robust oligodendrogenesis, similar to what we described previously using an intraspinal LPS microinjection model. Finally, a single co‐injection of E6020 with lysolecithin into spinal cord white matter increased axon sparing, accelerated myelin debris clearance, enhanced Schwann cell infiltration into demyelinated lesions, and increased the number of remyelinated axons. In vitro assays confirmed that direct stimulation of macrophages by E6020 stimulates myelin phagocytosis. These data implicate TLR4 signaling in promoting repair after CNS demyelination, likely by stimulating phagocytic activity of macrophages, sparing axons, recruiting myelinating cells, and promoting remyelination. This work furthers our understanding of immune–myelin interactions and identifies a novel synthetic TLR4 agonist as a potential therapeutic avenue for white matter demyelinating conditions such as spinal cord injury and multiple sclerosis.     

Varicella‐zoster virus encephalomyelitis with a prominent demyelinating component

The histopathologic presentation of varicella‐zoster virus (VZV) infection of the central nervous system is varied and is not well understood. Here we report a case of VZV encephalomyelitis with prominent demyelinating pathology in a patient with a history of follicular lymphoma treated with allogeneic stem cell transplantation. The patient presented with waxing and waning bilateral limb weakness and mental status changes. MRI showed leptomeningeal, peripheral spinal cord and periventricular cerebral white matter lesions in the brain, and polymerase chain reaction on cerebrospinal fluid detected VZV DNA. The patient expired from developing atrial fibrillation that rapidly progressed to ventricular fibrillation 10 days after admission to our hospital. Autopsy revealed macrophage‐rich areas of demyelination in the spinal cord and cerebrum with relative preservation of axons associated with inclusion bodies and positive immunostaining for VZV. This case represents a rare example of VZV encephalomyelitis presenting with a predominantly demyelinating, “multiple sclerosis‐like” pathology. The clinical and histopathologic findings and relevant literature are presented and discussed.     

A case of multiple sclerosis with polyradiculitis and spinal subarachnoid block

A case of 53-year-old female with multiple sclerosis was reported. In August 1987, she suffered from weakness in her legs and urinary retention. These signs had progressed with incomplete remissions and exacerbations. In March 1988, she developed sensory loss of all modalities below C2 level, spastic paralysis of upper extremities and flaccid paraplegia of lower extremities. Electromyography showed evidence of denervation in affected muscles of all extremities and paraspinal muscles. On lumber puncture, spinal fluid pressure fell to 0 mmH2O after removal of the spinal fluid of 12 ml, and the CSF protein was 740 mg/dl, indicating subarachnoid space block. The oligoclonal band was positive. MRI showed swelling in the cervical and upper thoracic cord, and multiple lesions in the periventricular white matter in the cerebrum. We diagnosed this case as multiple sclerosis in combination with acute polyradiculitis. The spinal subarachnoid block was considered to be caused by the swelling of the spinal cord.