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Human T cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is characterized by the generation of an intense CTL cell response directed against the viral transactivator protein Tax. In addition, patients diagnosed with HAM/TSP exhibit rapid activation and maturation of dendritic cells (DC), likely contributing to the robust, Tax-specific CTL response. In this study, extracellular Tax has been shown to induce maturation and functional alterations in human monocyte-derived DC, critical observations being confirmed in freshly isolated myeloid DC. Tax was shown to promote the production of proinflammatory cytokines and chemokines involved in the DC activation process in a dose- and time-dependent manner. Furthermore, Tax induced the expression of DC activation (CD40, CD80, and CD86) and maturation (CD83) markers and enhanced the T cell proliferation capability of DC. Heat inactivation of Tax resulted in abrogation of these effects, indicating a requirement for the native structure of Tax, which was found to bind efficiently to the DC membrane and was internalized within a few hours, suggesting that extracellular Tax may possess an intracellular mechanism of action subsequent to entry. Finally, inhibitors of cellular signaling pathways, NF-kappaB, protein kinase, tyrosine kinase, and phospholipase C, were shown to inhibit Tax-mediated DC activation. This is the first study reporting the immunomodulatory effects of extracellular Tax in the DC compartment. These results suggest that DC, once exposed to Tax by uptake from the extracellular environment, can undergo activation, providing constant antigen presentation and costimulation to T cells, leading to the intense T cell proliferation and inflammatory responses underlying HAM/TSP.

Vitamin B12 deficiency due to malnutrition or malabsorption may lead to pernicious anemia and neurological disorders. Although randomized prospective studies have shown that pernicious anemia can be safely treated with oral vitamin B12 even in the absence of intrinsic factor, it is still common practice to treat patients with neurological symptoms with intramuscular cyancobalamin injections. We report the successful oral treatment of subacute combined degeneration of the spinal cord in a 24-year-old woman closely monitored clinically with MRI and plasma levels of vitamin B12, homocysteine, and methylmalonic acid. We suggest monitored oral substitution therapy as first-line therapy for neurological disorders related to vitamin B12 deficiency.

We investigate the cytokine profile in the cerebrospinal fluid (CSF) and serum of patients with spinal cord schistosomiasis (SCS). Increased levels of IL-1beta, IL-4, IL-6 and IL-10 and low concentrations of TNF-alpha and IFN-gamma were observed in both CSF and serum. CSF showed higher levels of IL-4 and IL-6 when compared to the paired serum samples. A negative correlation between the concentrations of IL-10 and IFN-gamma was observed in the CSF. These findings suggest an inflammatory as well as a skewed type-2 immune response that probably occur both locally and systemically and may be involved in the pathogenesis of SCS.

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of not only adult T-cell leukemia but also HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Among the rat strains infected with HTLV-1, chronic progressive myelopathy, named HAM rat disease, occurs exclusively in WKAH rats. In the present study, we found that HTLV-1 infection induces interferon (IFN)-gamma production in the spinal cords of HAM-resistant strains but not in those of WKAH rats. Neurons were the major cells that produced IFN-gamma in HTLV-1-infected, HAM-resistant strains. Administration of IFN-gamma suppressed expression of pX, the gene critically involved in the onset of HAM rat disease, in an HTLV-1-immortalized rat T-cell line, indicating that IFN-gamma protects against the development of HAM rat disease. The inability of WKAH spinal cord neurons to produce IFN-gamma after infection appeared to stem from defects in signaling through the interleukin (IL)-12 receptor. Specifically, WKAH-derived spinal cord cells were unable to up-regulate the IL-12 receptor beta2 gene in response to IL-12 stimulation. We suggest that the failure of spinal cord neurons to produce IFN-gamma through the IL-12 pathway is involved in the development of HAM rat disease.

Background: Spinal cord injury and subsequent paraplegia remains an unpredictable and devastating complication of thoracoabdominal aortic surgery. The aim of this study was to investigate spinal cord injury due to prolonged thoracoabdominal aortic occlusion., Materials and Methods: We used a highly reproducible porcine model of 45-min thoracoabdominal aortic occlusion, which was accomplished by two balloon occlusion catheters. Neurological evaluation after the end of experiment was performed by an independent observer according to the Tarlov scale. The lower thoracic and lumbar spinal cords were harvested at 10, 48, and 120 h (n = 6 animals per time point) and examined histologically with hematoxylin and eosin (H&E) stain and TUNEL method. Tarlov scores, number of neurons, and the grade of inflammation were analyzed., Results: H&E staining revealed reduction in the number of motor neurons which occurred in two phases (between 0 and 10 h and between 48 and 120 h of reperfusion), as well as development of inflammation in spinal cord sections during the reperfusion period, reaching a peak at 48 h. TUNEL reaction was negative for apoptotic neurons at any time point., Conclusions: In this porcine model, we demonstrated that, after 45 min of thoracoabdominal aortic occlusion, motor neuron death seems to occur in two phases (immediate and delayed). Inflammation was a subsequent event of transient prolonged spinal cord ischemia and possibly a major contributor of delayed neuronal death. Using TUNEL straining we found no evidence of neuronal apoptosis at any time point of reperfusion.

Atopic dermatitis (AD) is frequently associated with intestinal and cervical lesions. Staphylococcus aureus produces many kinds of toxins, the bacterial superantigens. The detection rate of toxins was 80.1% from 196 S. aureus strains. Neurological examinations revealed abnormalities in 59 out of 81 AD patients. Cervical magnetic resonance imaging (MRI) was performed in 46 patients randomly and showed abnormal findings in 38 of these patients. In 23 patients who underwent MRI and duodenal biopsy, 3 were found to be normal neurologically and 2 patients showed normal duodenal tissue. However, 18 patients had abnormal findings both on neurological examination and in duodenal tissue. Serial duodenal biopsy tests were performed in 10 AD patients. In 5 patients, the findings of chronic duodenitis disappeared after the therapy with povidone-iodine. These data indicate that the therapy was effective not only for the skin lesions, but improved gastrointestinal tract lesions and cervical myelopathy, by eradicating bacterial superantigens.

Study Design: Case report., Objectives: A case report of spinal sarcoidosis improving clinically and radiographically with treatment which correlated with improvement in cerebrospinal fluid T-lymphocyte subpopulation ratios., Setting: Walter Reed Army Medical Center., Case Report: A 46-year-old man presented with an enhancing spinal cord lesion. Lymph node biopsy confirmed sarcoidosis, and cerebrospinal fluid (CSF) analysis showed elevation in the ratio of two T-lymphocyte subpopulations. Treatment with steroids resulted in clinical resolution and immunocytologic improvement in the CSF.

A small but relatively constant proportion (3-5%) of mice chronically infected with Mycobacterium lepraemurium (MLM) develops bilateral paralysis of the rear limbs. The aim of the study was to investigate whether or not the bilateral leg palsy results from nerve involvement. Direct bacterial nerve infection or acute/delayed inflammation might possibly affect the nerves. Therefore, palsied animals were investigated for the presence of: (a) histopathological changes in the leg tissues including nerves, bones and annexes, and (b) serum antibodies to M. lepraemurium and M. leprae lipids, including phenolic glycolipid I from M. leprae. Histopathological study of the palsied legs revealed that the paralysis was not the result of direct involvement of the limb nerves, as neither bacilli nor inflammatory cells were observed in the nerve branches studied. Antibodies to brain lipids and cardiolipin were not detected in the serum of the palsied animals, thus ruling out an immune response to self-lipids as the basis for the paralysis. Although high levels of antibodies to MLM lipids were detected in the serum of palsied animals they were not related to limb paralysis, as the nerves of the palsied legs showed no evidence of inflammatory damage. In fact, nerves showed no evidence of damage. Paralysis resulted from severe damage of the leg bones. Within the bones the bone marrow became replaced by extended bacilli-laden granulomas that frequently eroded the bone wall, altering the normal architecture of the bone and its annexes, namely muscle, tendons and connective tissue. Although this study rules out definitively the infectious or inflammatory damage of nerves in murine leprosy, it opens a new avenue of research into the factors that participate in the involvement or the sparing of nerves in human and murine leprosy, respectively.

In acute experimental autoimmune encephalomyelitis (EAE), demyelination is induced by myelin-specific CD4(+) T lymphocytes and myelin-specific antibodies. Recovery from the disease is initiated by cytokines which suppress T cell expansion and the production of myelin-toxic molecules by macrophages. Th2/3 cell-derived signals may also be involved in central nervous system (CNS) repair. Remyelination is thought to be initiated by the recruitment and differentiation of oligodendrocyte precursor cells (OPC) in demyelinated CNS lesions. Here, we report that unlike Th1 cytokines (TNF-alpha, IFN-gamma), the Th2/3 cytokine TGF-beta induces primary microglia from C57BL/6 mice to secrete a chemotactic factor for primary OPC. We identified this factor to be the hepatocyte growth factor (HGF). Our studies show that TGF-beta-1-2-3 as well as IFN-beta induce HGF secretion by microglia and that antibodies to the HGF receptor c-Met abrogate OPC chemotaxis induced by TGF-beta2-treated microglia. In addition we show spinal cord lesions in EAE induced in SJL/J mice to contain both OPC and HGF producing macrophages in the recovery phase, but not in the acute stage of disease. Taken these findings, TGF-beta may play a pivotal role in remyelination by inducing microglia to release HGF which is both a chemotactic and differentiation factor for OPC.

DBA/2 CrSlc mice infected with the D variant of encephalomyocarditis virus (EMC-D) (10 PFU/head) developed biphasic hind limb paralysis due to spinal cord lesion. The early phase lesion was characterized by demyelination with infiltration of macrophages in the funiculus lateraris and the late phase lesion by degeneration of motor neurons with infiltration of CD4(+) T cells in the cornu ventrale. In the present study, treatment with anti-Mac1 monoclonal antibody (MAb) or anti-CD4 MAb prior to virus infection (-3 to -1 days) reduced the early phase lesion and the incidence of the first paralysis. Signals of viral RNAs were observed only in a few oligodendrocytes in the funiculus lateraris. Treatment with anti-CD4 MAb from 31 to 33 days post infection when mice showed recovery from the first paralysis reduced the late phase lesion and prevented the second paralysis. Signals of viral RNAs were still detected in a few degenerated neurons in the cornu ventrale. These results indicate that while macrophages and CD4(+) T cells participate in the early phase lesion and paralysis and only CD4(+) T cells in the late phase lesion and paralysis.

Objective: The relationship between multiple sclerosis (MS) and Sjögren syndrome (SS) is controversial. Nine patients, previously diagnosed with primary progressive MS (PPMS) and who fulfilled the diagnostic criteria for SS, are described., Methods: The European classification criteria for SS were used to study nine PPMS patients that complained of sicca complex symptoms. The following tests were performed: Schirmer test, rose bengal staining, salivary scintigraphy, minor salivary gland biopsy and serologic tests (antibodies Ro/SS-A, La/SS-B and antinuclear antibodies)., Results: The nine patients met criteria to be diagnosed with SS (at least four criteria). All patients were women with a mean age of 46.6 years at symptom onset. Spastic paraparesis was the presenting symptom in all patients, and spinal cord magnetic resonance imaging (MRI) showed abnormalities in most; anti-Ro and anti-La antibodies were mostly negative., Conclusions: Some MS patients, predominantly women over 45 years of age, with progressive spastic paraparesis, antiextractable nuclear antigen antibodies (Ro/SS-A or La/SS-B) negative and with abnormalities in spinal cord MRI, may have SS as an additional or alternative diagnosis.

Invasive central nervous system aspergillosis is being seen with an increased frequency, particularly due to the increased number of immunosuppressed patients. The major cause of invasive central nervous system aspergillosis is bone marrow transplantation. In most cases, aspergillosis develops in the paranasal sinuses and in the lungs, and secondarily spreads to the brain. Imaging of cerebral aspergillosis may present different patterns depending on the lesion's age and the immunologic status of the patient. Lesions of the spinal cord are far less common but has been encountered in our series. In this article we review the clinical and radiologic features of aspergillosis affecting the central nervous system in patients who underwent bone marrow transplantation. Different CT and MR patterns are presented, including pertinent clinical and pathologic material. Significant morbidity and mortality can be associated with this fungal infection, and it is therefore incumbent upon the radiologist to identify intracranial aspergillosis as early as possible so that appropriate therapy can be administered.

Contributions of humoral and cellular immunity in controlling neurotropic mouse hepatitis virus persistence within the CNS were determined in B cell-deficient J(H)D and syngeneic H-2(d) B cell+ Ab-deficient mice. Virus clearance followed similar kinetics in all mice, confirming initial control of virus replication by cellular immunity. Nevertheless, virus reemerged within the CNS of all Ab-deficient mice. In contrast to diminished T cell responses in H-2(b) B cell-deficient muMT mice, the absence of B cells or Ab in the H-2(d) mice did not compromise expansion, recruitment into the CNS, or function of virus-specific CD4+ and CD8+ T cells. The lack of B cells and lymphoid architecture thus appears to manifest itself on T cell responses in a genetically biased manner. Increasing viral load did not enhance frequencies or effector function of virus-specific T cells within the CNS, indicating down-regulation of T cell responses. Although an Ab-independent antiviral function of B cells was not evident during acute infection, the presence of B cells altered CNS cellular tropism during viral recrudescence. Reemerging virus localized almost exclusively to oligodendroglia in B cell+ Ab-deficient mice, whereas it also replicated in astrocytes in B cell-deficient mice. Altered tropism coincided with distinct regulation of CNS virus-specific CD4+ T cells. These data conclusively demonstrate that the Ab component of humoral immunity is critical in preventing virus reactivation within CNS glial cells. B cells themselves may also play a subtle role in modulating pathogenesis by influencing tropism.

The slow immune response in the adult mammalian CNS results in slow myelin phagocytosis along degenerating white matter after injury. This has important consequences for axon regeneration because of the presence of axon growth inhibitors in myelin. In addition, abnormal immune cell responses in the CNS lead to demyelinating disease. Lysophosphatidylcholine (LPC) can induce an inflammatory response in the CNS, producing rapid demyelination without much damage to adjacent cells. In this study, we searched for the molecular switches that turn on this immune cell response. Using reverse transcription PCR analysis, we show that mRNA expression of macrophage inflammatory protein-1alpha (MIP-1alpha), macrophage chemotactic protein-1 (MCP-1), granulocyte macrophage-colony stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNF-alpha) in the spinal cord is rapidly and transiently upregulated after intraspinal injection of LPC. Neutralizing these signaling molecules with function-blocking antibodies suppresses recruitment of T-cells, neutrophils, and monocytes into the spinal cord, as well as significantly reduces the number of phagocytic macrophages and the demyelination induced by LPC. These findings will have important implications for CNS regeneration and demyelinating disease.

Although infectious myelopathies are rare, appropriate aetiological diagnosis is of crucial importance to improve outcome. Lyme disease causes a myelomeningoradiculitis during the second stages and a progressive encephalomyelitis during the third stage. Serum and cerebrospinal fluid antibody tests are the basis of diagnosis. Myelopathy usually responds to treatment with ceftriaxone or doxycycline. Vacuole myelopathy occurs in patients with human immunodeficiency virus infection. It is characterised by a progressive spastic and ataxic paraparesis. About half of patients have symptoms of dementia. No specific treatment is available. Human T-cell lymphotropic virus type I is endemic in tropical areas and particularly in French West Indies. It causes a chronic spastic paraparesis with sexual and bladder dysfunction. Diagnosis depends on the positive antibody response in both serum and cerebrospinal fluid, and on the exclusion of other causes of spinal cord disease. There is no specific treatment.

Macrophage migration inhibitory factor (MIF) is becoming increasingly recognized as an important regulator of immune and inflammatory responses. It is released by activated T lymphocytes and macrophages and up-regulates the proinflammatory activity of these cells. MIF is required for antigen- and mitogen-driven T cell activation, and stimulates macrophages to release cytokines and nitric oxide. On the basis of the recent suggestion that pharmacological modulation of MIF production and neutralization of its activity may have important implications for treatment of a variety of autoimmune or inflammatory conditions, we determined the level of MIF in the cerebrospinal fluid (CSF) of patients with conventional-form multiple sclerosis (C-MS) and optic-spinal form multiple sclerosis (OpS-MS), and neuro-Behçet's disease (NBD). As control, the CSF of patients with non-inflammatory neurological diseases (NIND) was used. The concentration of MIF in CSF samples was significantly elevated in relapsed cases of C-MS (4.13+/-1.07 ng/ml) (mean+/-S.D.) compared with control samples (2.38+/-0.60 ng/ml) (P<0.0001), whereas MIF in the CSF of C-MS patients in remission was not elevated (2.65+/-0.67 ng/ml). The concentration of MIF in the CSF of OpS-MS patients in relapse (5.53+/-1.74 ng/ml) was higher than that of patients with C-MS in relapse (P<0.05). In NBD patients, the concentration of MIF in CSF was significantly elevated (7.47+/-5.61 ng/ml) compared with control samples (P<0.01) and correlated well with cell count in these samples (r=0.910, P<0.005). These results suggest that MIF may play a pivotal role in immune-mediated diseases of the central nervous system, and that MIF may be useful in the study of differences between C-MS and OpS-MS.

Weber-Christian disease is an inflammatory disorder of fatty tissue which usually presents with raised red tender nodules in the skin. Although there may be additional systemic upset, there are very few reports of neurological features associated with this condition. We report a patient with biopsy-confirmed systemic Weber-Christian disease in whom a transient partial myelopathy, of probable inflammatory origin, was the most prominent feature. Based on recent reports of the effects of immune mediators on neuronal function, a possible pathogenetic explanation for this syndrome is suggested.

Although the principal neuropathological feature of human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) is chronic inflammation of the spinal cord, characterized by perivascular cuffing of mononuclear cells accompanied by parenchymal lymphocytic infiltration, the precise mechanisms by which HTLV-I infection causes chronic inflammation of the spinal cord are still obscure. In patients with HAM, peripheral blood CD4(+)T lymphocytes, particularly HTLV-I-infected CD4(+)T lymphocytes, have increased adherent activity to endothelial cells and transmigrating activity through basement membranes. In addition, the profile of cytokine expression suggests increased numbers of Th1 cells in peripheral blood CD4(+)T lymphocytes of patients with HAM. These findings strongly suggest that immune deviation toward Th1, which might be based on high viral load of HTLV-I, plays an important role in tissue damage in the central nervous system of patients with HAM. We herein emphasize the importance of activated Th1 cells as the first trigger in the immunopathogenesis of HAM., (Copyright 2000 Harcourt Publishers Ltd.)

Recent pathological studies have re-emphasized that axonal injury is present in patients with multiple sclerosis, the most common demyelinating disease of the CNS in humans. However, the temporal profile of demyelination and axonal loss in multiple sclerosis patients and their independent contributions to clinical and electrophysiological abnormalities are not completely understood. In this study, we used the Theiler's murine encephalomyelitis virus model of progressive CNS inflammatory demyelination to demonstrate that demyelination in the spinal cord is followed by a loss of medium to large myelinated fibres. By measuring spinal cord areas, motor-evoked potentials, and motor coordination and balance, we determined that axonal loss following demyelination was associated with electrophysiological abnormalities and correlated strongly with reduced motor coordination and spinal cord atrophy. These findings demonstrate that axonal loss can follow primary, immune-mediated demyelination in the CNS and that the severity of axonal loss correlates almost perfectly with the degree of spinal cord atrophy and neurological deficits.

By analogy with other infections of the central nervous system (CNS), it is believed that schistosomal myeloradiculopathy (SMR) is an entity that may involve a mild-to-moderate degree of impairment of the blood-brain barrier along with intrathecal synthesis of antibodies. The first of these aspects is obvious but the second has not been clearly demonstrated. This study was undertaken in Brazil with the aim of investigating the production of immunoglobulin G (IgG) within the CNS in patients with SMR, by the determination of the cerebrospinal fluid (CSF) IgG index. The study population included 54 patients with SMR, evaluated prospectively. The CSF IgG index was increased in 43 of them (80%). Preliminary results from our laboratory suggest that these antibodies are reactive against Schistosoma mansoni antigens. Thus, this finding also suggests that this index may be useful in the differential diagnosis of SMR.

The optic-spinal form of multiple sclerosis (OSMS), characterized by recurrent involvement of optic nerve and spinal cord with rare brain magnetic resonance imaging lesions, is relatively common among Asians. While individual cases of OSMS with anti-thyroid autoantibodies (ATABs) have been reported, the frequency of ATAbs in OSMS and classical multiple sclerosis has not been studied. We studied serum ATAbs and anti-nuclear antibodies (ANA) in 46 Japanese patients with multiple sclerosis: 14 with OSMS, and 32 with non-OSMS. Six patients were positive for ATAbs: five women with OSMS and one man with non-OSMS. The frequency of ATAbs in OSMS (5/14) was significantly higher than that in non-OSMS (1/32; P = 0.007), but the frequency of ANA did not differ between OSMS (3/14) and non-OSMS (6/32; P = 0.99). There may be a pathogenetic link between anti-thyroid autoimmunity and a subgroup of OSMS in Japanese.

Inflammation of multiple sclerosis (MS) brain and spinal cord tissue consists of macrophages, T lymphocytes and cytokines as well as B lymphocytes and immunoglobulins (IgGs). IgG can be detected in high concentrations in both central nervous system tissue and cerebrospinal fluid (CSF). Using a sensitive radioimmunoassay (RIA), autoantibodies to myelin basic protein (anti-MBP) can be detected in the CSF of 90-95% of MS patients with active disease. The purpose of the present report was to determine whether these same autoantibodies can be reliably detected in non-MS patients. Between 1978 and 1998, CSF was collected from 1,968 control non-MS patients with psychiatric, inflammatory and noninflammatory neurological diseases as well as nonneurological systemic diseases, and anti-MBP were measured by the same RIA used to detect anti-MBP in MS CSF. Anti-MBP were undetectable in 98% of CSF samples from non-MS controls. In the remaining 2% of control samples, CSF IgGs capable of binding to MBP in vitro were unpredictably detected. This latter group included 1% of patients with miscellaneous diseases such as encephalomyelitis, 5 siblings with familial spastic paraparesis, rare patients with strokes, Wernicke-Korsakoff's syndrome, inherited leukodystrophy, motor neuron disease and some patients with miscellaneous spinal cord diseases. An additional 1% of patients included a group with neurological symptoms suggestive of early or predisseminated MS. The high prevalence of free and/or bound anti-MBP in the CSF of MS patients and the rare and unpredictable occurrence in the CSF of non-MS patients suggest that autoimmunity to MBP may be operative in the demyelination of MS. Molecular clones of anti-MBP with specificity towards variable surface or cryptic MBP epitopes in vivo may determine whether or not they are involved in the demyelinating process, and this variability may also be present within the MS population. Potential mechanisms of anti-MBP-mediated demyelination in MS patients are discussed.

Chronic or recurrent urinary tract infection (UTI) is a significant problem or patients with spinal cord lesions (SCL). UTIs are thought to be a major factor in the development of reduced renal function. To investigate the pathogenesis 151 patients with SCL were included in this study during a 7 year period. Results of intravenous pyelography and isotope renography were recorded as well as the bladder emptying methods. One to seven blood samples were obtained from each patient and tested for plasma creatinine, and the presence of precipitating antibodies against Escherichia coli, Klebsiella pneumonia, Klebsiella ozaenae, Proteus mirabilis, Enterococcus faecalis and Pseudomonas aeruginosa. We found significant correlation between duration of SCL and precipitating antibodies against urinary tract pathogens (PAU) (r = 0.23, P < 0.005), between plasma creatinine and PAU in patients with spina bifida (r = 0.64, P < 0.01), between PAU and the number of positive urine cultures (r = 0.17; P < 0.05) and a relation between abnormal urological findings and PAU. In addition, the PAU was significantly higher in patients with indwelling urethral catheters (P < 0.001). Thus it seems that PAU can be of prognostic value in SCL patients, and PAU might be an indicator for intensified treatment of recurrent UTI.

In three patients with recurrent episodes of acute transverse myelopathy, spinal MR imaging during each episode showed areas of hyperintensity on proton density- and T2-weighted images with inconsistent contrast enhancement. Cranial MR imaging, laboratory screenings, and CSF analysis showed only increased titers of anticardiolipin antibodies. Although a causative role in neurologic conditions has not been established conclusively, an association between these antibodies and acute transverse myelopathy and its recurrences cannot be ignored.

In AIDS, pathology in the spinal contents usually follows that in the brain but is less frequent. Opportunistic infections are found in an average of 9.5% of spinal AIDS autopsies but in 54% of autopsies of the whole CNS. Necrotizing CMV radiculomyelitis is a rare (3.4% in spinal autopsies) but very characteristic opportunistic spinal lesion. The most prominent spinal cord disease in AIDS is vacuolar myelopathy, occurring in greatly differing frequencies according to different geographical areas, with a mean of about 22.5% in AIDS spinal cord autopsies. Its pathogenesis and clinicopathologic correlation need clarification; it appears to develop mainly in severely ill AIDS patients with significant viral load, advanced immunosuppression, and confounding metabolic imbalance.

We herein describe 4 adult patients with upper cervical myelitis presenting with paresthesia in the distal parts of all four limbs and who also all had hyperIgEemia. Two of them had full-blown atopic dermatitis at the time of neurologic illness, while the others had a preceding history of atopic dermatitis. All showed high signal intensity lesions at either the C3 or C4 segment, which mainly affected the posterior column on the T2-weighted spinal cord magnetic resonance imaging. All patients had specific IgE antibodies to two mite antigens and their onset of myelitis coincided with the seasonal increase of the mite antigens in Japan. Therefore, it is possible that the atopic conditions with hyperIgEemia in these patients may thus have contributed to the development of myelitis.

Central nervous system involvement in systemic lupus erythematosus (SLE) is frequent and severe, however, myelopathy is rarely reported (0.8 p. 100 of SLE cases). We describe two SLE-young women. They were 21 and 37 year old, presented with acute paraplegia. CSF study showed pleocytosis and moderately elevated protein. Antinuclear, anti-DNA and anticardiolipin were positive. High dose steroids therapy induced marked improvement. The pathogenesis of myelopathy in SLE remains unclear. Anti-phospholipid antibodies may cause thrombosis and ischemic myelopathy. However, auto-antibodies directed against central nervous system constituents may be involved.

A 60-year-old woman was admitted to our hospital with bilateral weakness of the lower limbs. She had been suffering from spastic paraparesis of unknown origin for 12 years since she was 48. Myelopathy with the Th6 level appeared when she was 52 and underwent gradual deterioration. On admission, she showed spastic paraparesis and myelopathy with the Th6 level. A thoracic spinal MRI examination revealed a wholly thin spinal cord. EMG demonstrated that the conduction velocity of the peroneal nerve was 37.8m/sec, and F waves were not evoked on stimulation of the peroneal nerve. Although the anti-GM1 and anti-GD1b antibody titers in the serum were increased on admission, their values decreased transiently after whole plasmapheresis. There was accompanying impairment of the radiculoneuropathy and myelopathy. It is important to measure the titers of anti-ganglioside antibodies in patients with myeloradiculoneuropathy of unknown origin, and whole plasmapheresis is considered to represent a useful treatment for this type of illness.

The purpose of this study was to examine the distribution of immunoglobulin and complement component C3 in spinal cord tissues of dogs with degenerative myelopathy. Sections of formalin-fixed paraffin-embedded spinal cord from five German Shepherd dogs with clinical and histological features consistent with degenerative myelopathy (DM) and one normal dog were tested immunohistochemically for deposition of immunoglobulin G (IgG) and the third component of complement (C3). In all dogs there was staining associated with large and small blood vessels. In addition, in the dogs with DM there was focal staining for IgG and C3 in spinal nerve tracts characteristically affected in DM. Deposition of IgG and C3 was found in histological lesions, and in addition, in other areas independent of visible lesions, suggesting that IgG and C3 deposition may precede histological evidence of spinal cord damage. These findings suggest a role for immune-mediated destruction of the spinal cord which may contribute to the pathogenesis of DM in German Shepherd dogs.

The specificity for GFAP (glial fibrillary acidic protein) of oligoclonal IgG bands in the CSF of a patient with acute myelitis was demonstrated by isoelectric focusing and affinity blotting. Findings were confirmed by western blotting using a monoclonal antibody to GFAP as a reference. Immune reactions to this astrocyte protein are considered as arising secondary to spinal cord tissue lesion.

We evaluated the presence of soluble intercellular adhesion molecule-1 (sICAM-1) antigen in the sera of patients with multiple sclerosis and human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) using an enzyme-linked immunosorbent assay. Patients with multiple sclerosis in the active phase had higher sICAM serum levels than did control subjects (p < 0.01). In addition, a significantly increased serum level of sICAM-1 was found in patients with HAM (p < 0.001). Furthermore, we found a positive correlation with HAM sICAM-1 and tumor necrosis factor-alpha levels in the sera of patients with multiple sclerosis in the active phase (r = 0.88, p < 0.01) and in those with HAM (r = 0.86, p < 0.01). These results suggest that serum sICAM-1 may be related to clinical activity in patients with multiple sclerosis and the detection of sICAM-1 could be useful as a marker of inflammatory disease.

Vacuolar myelopathy belongs to the AIDS-associated diseases. It is characterized by vacuolation and infiltration of the long tracts of the spinal cord by macrophages. The clinical and morphological findings of 8 AIDS-patients with vacuolar myelopathy are reported here. The syndrome developed during the final stages of AIDS and was associated with HIV-encephalopathy in 5 cases. The vacuoles were mainly due to intramyelinic swelling and vacuolation. Vacuolated macrophages and axons contributed only to a minor degree. In one case only, HIV-antigens were detected immunohistochemically. The results are discussed in the light of modern pathogenetical concepts of HIV-related diseases.

We studied magnetic resonance imaging (MRI) of the head and cervical spine and CT of the head in 46 patients (14 men, 32 women) with chronic progressive myeloneuropathy. The findings were correlated with human T-lymphotropic virus type I (HTLV-I) serology, race, country of origin, and age. We found a female predominance of 2:1. Most patients were aged between 30 and 50 years, and most were Caribbean immigrants and black. There were 9 men and 17 women with blood antibody titers to HTLV-I and 7 men and 15 women with cerebrospinal fluid (CSF) titers. All patients with virus or antibodies in blood or CSF were Caribbean immigrants or black. T2-weighted cranial MRI showed scattered areas of high signal intensity in the cerebral white matter, usually in the periventricular and subcortical areas, but not in the posterior cranial fossa. Cranial CT revealed periventricular low density areas, ventricular enlargement, and atrophy MRI of the cervical spine showed atrophy of the cord. Myelography was normal in all 15 patients examined. No imaging differences were observed between the HTLV-I-positive and -negative patients. These findings, although consistent with demyelination, are not specific.

Progressive necrotic myelopathy is a syndrome characterized by a spotty necrotic degeneration of the whole spinal cord in both anterior and posterior horns. This syndrome was recorded in a man suffering from a lymphoplasmatocytoid lymphoma. Whilst the usual evolution of this neurological syndrome is inexorably fatal, our case had a better outcome, due to the good response of the neoplasm to therapy. Progressive necrotic myelopathy is an uncommon complication of cancer, but it is probably incorrectly recognized in a number of cases. Two possible pathogenetic hypotheses are suggested: an autoimmune or an infective mechanism.

Unexplained spastic myelopathy in black (Zulu) patients, similar to that seen in the tropics, has previously been described from Natal, South Africa. Following reports linking the human T cell lymphotropic virus type I (HTLV-I) to spastic myelopathy, we undertook a prospective and retrospective search for HTLV-I antibodies in 36 patients who were labelled as having unexplained myelopathy; 24 (66%) were positive and HTLV-I was isolated from 4 out of the 6 patients whose peripheral blood lymphocytes were cultured. Eighteen (75%) gave a short history (less than 6 months). There was a female preponderance (71%), spinothalamic dysfunction was common (55%) and as many as half were severely disabled (50% wheelchair bound). Routine laboratory studies showed no specific trends apart from hypergammaglobulinaemia and CSF pleocytosis (greater than 5 cells/microliter in 66% of patients). The total CSF protein was raised (greater than 0.4 g/l) in 45% of patients. The IgG index was greater than 0.7 in 15 of 19 patients. Conventional myelography did not show any specific abnormalities. Computer assisted myelography was undertaken in 22 patients; 3 showed arachnoiditis and 2 spinal cord atrophy. Periventricular lucencies were seen in 1 of 10 patients who had computed tomography of the head. Nerve conduction studies demonstrated abnormalities in 46% of the patients indicating that subclinical peripheral nerve dysfunction was common. Visual evoked responses were abnormal in only 1 patient but brainstem auditory evoked response studies showed some abnormality in 42% of the patients. The finding of HTLV-I antibodies in a significant number, and the isolation of HTLV-I from the blood in 6 of our black patients with noncompressive myelopathy, represents a substantial clinical advance. Future studies should define more clearly the role of the virus in this disorder.

A 52-year-old human immunodeficiency virus type 1-seropositive bisexual black man was evaluated at UCLA because of the recent onset of progressive lower-extremity weakness. Initial neurologic examination showed that the patient's distal weakness was greater than his proximal weakness, with bilateral foot drop and electrophysiologic evidence of denervation in the distal lower extremities. Magnetic resonance imaging of the brain and spinal cord disclosed no abnormalities. Subsequent neurologic evaluation 8 months later showed a myelopathy, with progression of lower-extremity weakness, spasticity, and flexor spasms, and urinary incontinence, as well as the peripheral neuropathy noted previously. A second magnetic resonance imaging scan of the brain showed patchy foci of increased signal intensity in white matter and cortex, with mild generalized cerebral and cerebellar atrophy and no lesions in the spinal cord. Specimens of the patient's serum and cerebrospinal fluid contained antibodies to human immunodeficiency virus type 1. Additionally, specimens of his serum and cerebrospinal fluid were tested for antibody to human T-cell leukemia virus type I by Western blotting and radioimmunoprecipitation, and found to be positive for human T-cell leukemia virus type I gag, env, and tax antibodies. The primary cause of severe myelopathy in this patient may be infection with human T-cell leukemia virus type I rather than with human immunodeficiency virus type 1. Treatment with prednisolone resulted in improvement of the lower-extremity weakness, reduction in flexor spasms, and slower but significant improvement in urinary symptoms. Patients who are infected with human immunodeficiency virus type 1 and have unusual motor findings should be tested for concomitant human T-cell leukemia virus type I infection.

The CNS pathology of 10 autopsy cases of Japanese HAM/TSP patients with a serological confirmation of HTLV-I infection was reviewed. The essential histopathological feature was a chronic progressive inflammatory process with marked parenchymal exudation of lymphocytes and monocytes into both the grey and white matter of the spinal cord, uniquely perpetuating for more than 3 years after the onset of neurological symptoms, and resulting in severe degeneration of the white matter accompanied by marked glio-mesenchymal tissue reactions. Both the inflammation and the white matter degeneration were most conspicuous in the lower thoracic cord. The lateral column was always and most severely affected. Although the parenchymal tissue degeneration was not confined to any particular long tracts, symmetrical degeneration of the lateral pyramidal tract was evident in all cases. Diffuse myelin pallor was also seen in the anterior column but it was usually mild. The posterior column was commonly involved but the severity and extent of the white matter degeneration were variable. Neurons were relatively well preserved. These histopathological features of HAM/TSP in Japan largely agree with those previously described for HAM/TSP in tropical regions. In the absence of detectable amount of HTLV-I antigens at the sites of inflammation, "chronic progressive parainfectious myelitis" seems to be the most appropriate descriptive term for this unique histopathology of HAM/TSP.

Aspergillus is the most common fungal infectious pathogen in immunocompromised individuals, but the diagnosis is hard to obtain. In a patient with spinal cord involvement, MRI proved to be excellent.

Paired cerebrospinal fluid (CSF) and serum samples from 52 Italian patients affected by myelopathy of unknown origin (MUO) were tested for the presence of antibodies to human T cell lymphotrophic virus type I (HTLV-I) by an enzyme-linked immunosorbent assay, in an attempt to demonstrate a common retroviral origin of MUO, tropical spastic paraparesis (TSP) and HTLV-I-associated myelopathy (HAM). All the patients complained of weakness to the legs, while weakness to the arms, mild sensory disturbances, impaired bladder and bowel functions, and impotence were present in different percentages. All CSF and serum samples were devoid of HTLV-I antibodies. The possible relations between MUO, TSP and HAM are discussed.

Prevention of experimental allergic encephalitis in SJL/J [H-2s] mice was achieved with in vivo administration of antibody reactive with I-As gene products prior to immunization with spinal cord antigen. No protection was evident in animals that received antisera specific for I-Js gene products. Administration of antibody to I-As beginning 5 days after immunization with spinal cord antigen delayed, but did not prevent, the onset of experimental allergic encephalitis.

Six adult patients had a chronic progressive myelopathy that possessed the following features: high antibody titers to human T-lymphotropic virus type I (HTLV-I) in serum and cerebrospinal fluid (CSF); predominantly upper motor neuron disorder, symmetrical, with mild sensory and bladder disturbances; and presence of adult T-cell leukemia-like cells in both peripheral blood and CSF. We refer to this entity as HTLV-I-associated myelopathy (HAM). Electrophoretic studies of immunoglobulin G in CSF using Western blot analysis characteristically demonstrated p24 and p32 bands. Rates of intra-blood-brain barrier synthesis were determined and found increased in the patients with HAM. Corticosteroid treatment produced clinical improvement in all of 4 patients. A retrospective survey of CSF samples was carried out in 287 patients with neurological disorders, and 6 additional patients with HAM were identified.

To determine factors affecting major histocompatibility complex (MHC) molecule expression in situ in the human central nervous system (CNS) cryostat tissue sections from 36 autopsies and four biopsies were stained by immunoperoxidase with antibodies to class I (HLA-alpha chain, beta-2 microglobulin), class II (HLA-DR, HLA-DQ) MHC, lymphocyte, and macrophage antigens and Factor VIII-related antigen (VIII-RA). Stained cells and vessels/mm2 were counted in gray and white matter of four CNS anatomic levels. Class I molecules were found on parenchymal and endothelial cells (approximately 50% of VIII-RA + vessels) but not neurons, and were more abundant in gray than white matter (p less than 0.02). Class I molecules were absent in infants, but in adults expression was unaffected by age, sex, postmortem interval, presence of CNS lesions, or systemic illnesses. Expression of HLA-alpha chain and beta-2 microglobulin were the same. Class II molecules were usually absent but were found on parenchymal and endothelial cells in older adults, most frequently in association with macrophage infiltrates and spinal cord tract degenerations, but not with systemic illnesses. Expression of HLA-DR was greater than that of HLA-DQ. In the human CNS, regulation regulation of expression of MHC molecules is complex, can be affected by age, regional anatomy, and by local or remote CNS lesions, and may influence patterns and degrees of T cell immune responses.