Cortical and Subcortical Dysmetabolism Are Dynamic Markers of Clinical Disability and Course in Anti-LGI1 Encephalitis.

BACKGROUND AND OBJECTIVES: This [18F]fluorodeoxyglucose (FDG) PET study evaluates the accuracy of semiquantitative measurement of putaminal hypermetabolism in identifying anti-leucine-rich, glioma-inactivated-1 (LGI1) protein autoimmune encephalitis (AE). In addition, the extent of brain dysmetabolism, their association with clinical outcomes, and longitudinal metabolic changes after immunotherapy in LGI1-AE are examined. METHODS: FDG-PET scans from 49 age-matched and sex-matched subjects (13 in LGI1-AE group, 15 in non-LGI1-AE group, 11 with Alzheimer disease [AD], and 10 negative controls [NCs]) and follow-up scans from 8 patients with LGI1 AE on a median 6 months after immunotherapy were analyzed. Putaminal standardized uptake value ratios (SUVRs) normalized to global brain (P-SUVRg), thalamus (P/Th), and midbrain (P/Mi) were evaluated for diagnostic accuracy. SUVRg was applied for all other analyses. RESULTS: P-SUVRg, P/Th, and P/Mi were higher in LGI1-AE group than in non-LGI1-AE group, AD group, and NCs (all p < 0.05). P/Mi and P-SUVRg differentiated LGI1-AE group robustly from other groups (areas under the curve 0.84-0.99). Mediotemporal lobe (MTL) SUVRg was increased in both LGI1-AE and non-LGI1-AE groups when compared with NCs (both p < 0.05). SUVRg was decreased in several frontoparietal regions and increased in pallidum, caudate, pons, olfactory, and inferior occipital gyrus in LGI1-AE group when compared with that in NCs (all p < 0.05). In LGI1-AE group, both MTL and putaminal hypermetabolism were reduced after immunotherapy. Normalization of regional cortical dysmetabolism associated with clinical improvement at the 6- and 20-month follow-up. DISCUSSION: Semiquantitative measurement of putaminal hypermetabolism with FDG-PET may be used to distinguish LGI1-AE from other pathologies. Metabolic abnormalities in LGI1-AE extend beyond putamen and MTL into other subcortical and cortical regions. FDG-PET may be used in evaluating disease evolution in LGI1-AE. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that semiquantitative measures of putaminal metabolism on PET can differentiate patients with LGI1-AE from patients without LGI1-AE, patients with AD, or NCs.

Clinical and immunological differences between MOG associated disease and anti AQP4 antibody-positive neuromyelitis optica spectrum disorders: Blood-brain barrier breakdown and peripheral plasmablasts.

BACKGROUND: Patients with anti-aquaporin-4 (AQP4) water channel antibody-positive neuromyelitis optica spectrum disorders (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein (MOG) associated disease (MOGAD) often present with similar clinical symptoms, and some cases are hard to differentiate at the time of onset. In this study, we compared the clinical characteristics, cerebrospinal fluid (CSF) analysis parameters, and peripheral T/B lymphocyte subsets during the active and chronic phases in AQP4-NMOSD and MOGAD. METHODS: A total of 17 MOGAD cases and 24 AQP4-NMOSD cases were studied. The clinical characteristics in both groups were summarized, including disease duration, total number of attacks, lesions, prevention of relapse during remission, and CSF analysis results during the active phase. T/B lymphocyte subsets were further investigated in the active and chronic phases. RESULTS: In the comparative study on clinical symptoms, a large proportion of optic neuritis was unilateral in MOGAD. In the comparative study on CSF analysis, protein level was significantly lower in MOGAD compared with AQP4-NMOSD (p = 0.006); myelin basic protein was significantly lower in MOGAD compared with AQP4-NMOSD (p = 0.04); albumin quotient was significantly lower in MOGAD compared with AQP4-NMOSD (p = 0.02); and IgG Quotient was significantly lower in MOGAD compared with AQP4-NMOSD (p = 0.05). In the analysis of T/B lymphocyte subsets, plasmablasts of the B cell subset in the active phase were significantly lower in MOGAD (2.1 ± 2.4) compared to AQP4-NMOSD (7.8 ± 7.2) (p < 0.05). In the chronic phase, transitional B cells were significantly higher in MOGAD (2.1 ± 1.8) compared to AQP4-NMOSD (0.6 ± 0.4) (p < 0.01). CONCLUSION: Clinical characteristics of MOGAD were similar to those of AQP4-NMOSD, but increased blood brain barrier permeability was suggested to be less severe in MOGAD compared to AQP4-NMOSD from CSF analysis. Furthermore, the pathogenesis of the two diseases was clearly distinct as plasmablasts in the active phase were not elevated in MOGAD, but were increased in AQP4-NMOSD.

MOG-IgG-associated demyelination: focus on atypical features, brain histopathology and concomitant autoimmunity.

INTRODUCTION: Antibodies to myelin oligodendrocyte glycoprotein (MOG) have been demonstrated in patients with optic neuritis (ON), encephalitis and myelitis. OBJECTIVE: To describe the clinical and paraclinical features in patients with MOG-associated demyelination, focusing on unusual cases, brain biopsy and concomitant autoimmunity. METHODS: A single centre retrospective observational case series, analysing demographic, clinical, laboratory, histopathology and radiological data from MOG- positive patients. RESULTS: We identified 20 adults. The male/female ratio was 1.5. Mean age at onset was 31.6 years and mean disease duration was 7.5 years. The most frequent presentation was myelitis (45%), followed by ON (30%). One case had simultaneous myelitis and ON. Two patients had a cortical syndrome, 1 patient had an encephalopathic presentation and 1 cryptogenic focal epilepsy. Anti-neutrophil cytoplasmic antibodies (ANCA) were found in 3 cases, while 1 patient had an antibody to glutamic acid decarboxylase (GAD). Brain biopsy was performed in 2 patients. Relapsing course was identified in 60% of patients. We also discuss 3 cases with atypical features, brain histopathology and concomitant autoimmunity. CONCLUSION: MOG- associated demyelination represents a new disease entity. Unusual cases are reported, expanding the disease spectrum. Elucidating this further should be the focus of prospective studies.

Prognostic indicators of improvement with therapeutic plasma exchange in pediatric demyelination.

OBJECTIVES: To determine the safety and clinical benefit of therapeutic plasma exchange (TPE) as rescue therapy in children with acute inflammatory demyelinating CNS syndromes and to identify baseline prognostic indicators of treatment improvement. METHODS: This single-center retrospective pediatric cohort included all consecutive patients admitted to our hospital over the period from 2003 to 2017 because of a steroid-refractory acute CNS event presumed to be inflammatory who required TPE. Functional status assessment to identify improvement included the following performance category scales: visual outcome, bladder control, gait, and Expanded Disability Status Scale (EDSS). These assessments were performed before and after TPE in every patient. RESULTS: Sixty-five children requiring TPE to treat 78 CNS attacks were included for analysis. Median age at TPE was 10.5 years (1.9-18 years); 45% were girls. Seropositivity (aquaporin-4 water channel-immunoglobulin G [IgG] or myelin oligodendrocyte glycoprotein-IgG) was found in 20 of 42 (48%) patients. Attack phenotypes leading to TPE were optic neuritis (ON) in 42%, longitudinally extensive transverse myelitis (LETM) in 31%, ON + LETM in 15%, and other combined syndromes in 11%. Overall, moderate to marked neurologic improvement was observed in 72% of children at the end of TPE and in 88.5% at 6 months of follow-up. Lower baseline scores on the EDSS, visual outcome, and gait scales were found to be independent prognostic indicators of treatment benefit. Sex, age at onset and at TPE, attack phenotype, disease duration, and time from attack onset to TPE initiation were not significantly associated with treatment outcome. Adverse events were observed in 31 of 524 (5.9%) procedures, being severe in 4. CONCLUSIONS: TPE was an effective rescue therapy associated with functional improvement. No therapeutic window for TPE initiation was identified in this pediatric cohort. Overall frequency of adverse events was low; however, serious events should be anticipated and avoided. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for children with acute inflammatory demyelinating CNS syndromes, TPE leads to functional improvement.

Ocular flutter as presenting manifestation of pediatric MOG antibody-associated demyelination: A case report.

A 13-year-old girl presented with a 5-day history of oscillopsia. On examination, ocular flutter and mild cerebellar signs were found. Brain magnetic resonance imaging (MRI) revealed four periventricular and subcortical non-enhancing lesions. Cerebrospinal fluid (CSF) oligoclonal bands were negative. Neuroblastoma or other malignancies were not found. She responded well to a corticosteroid-intravenous immunoglobulin (IVIG) combination and remained symptom-free for 3 years until presenting again with isolated ocular flutter. Brain MRI at this time remained atypical for classic multiple sclerosis (MS) with a predominance of juxtacortical demyelinating lesions. CSF was positive for oligoclonal bands. Serum myelin oligodendrocyte glycoprotein (MOG) antibodies were present. Ocular flutter can be the presenting feature of MOG antibody-associated pediatric demyelination.

The coexistence of recurrent cerebral tumefactive demyelinating lesions with longitudinally extensive transverse myelitis and demyelinating neuropathy.

Combined central and peripheral demyelination (CCPD) is a rare chronic inflammatory disorder of the nervous system. In this article, we report on a CCPD patient with a very unusual pattern of central demyelination, comprising recurrent cerebral tumefactive demyelinating lesions (three times, each one in a new area of the brain) and one episode of longitudinally extensive transverse myelitis. This patient could not be classified as having multiple sclerosis, or neuromyelitis optica spectrum disorder, or any other well-known inflammatory disorder of the central nervous system, associated with demyelinating neuropathy. A diagnosis of idiopathic inflammatory demyelinating disorder (IIDD) was made while waiting for more knowledge concerning the diseases currently characterized as IIDD.

Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination.

OBJECTIVE: We characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination. METHODS: We evaluated clinical phenotypes, annualised relapse rates (ARR) prior and on immunotherapy and Expanded Disability Status Scale (EDSS), in 218 demyelinating episodes from 33 paediatric and 26 adult patients. RESULTS: The most common initial presentation in the cohort was optic neuritis (ON) in 54% (bilateral (BON) 32%, unilateral (UON) 22%), followed by acute disseminated encephalomyelitis (ADEM) (20%), which occurred exclusively in children. ON was the dominant phenotype (UON 35%, BON 19%) of all clinical episodes. 109/226 (48%) MRIs had no brain lesions. Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses <10 mg daily or within 2 months of cessation. Immunotherapy, including maintenance prednisone (P=0.0004), intravenous immunoglobulin, rituximab and mycophenolate, all reduced median ARRs on-treatment. Treatment failure rates were lower in patients on maintenance steroids (5%) compared with non-steroidal maintenance immunotherapy (38%) (P=0.016). 58% of patients experienced residual disability (average follow-up 61 months, visual loss in 24%). Patients with ON were less likely to have sustained disability defined by a final EDSS of ≥2 (OR 0.15, P=0.032), while those who had any myelitis were more likely to have sustained residual deficits (OR 3.56, P=0.077). CONCLUSION: Relapsing MOG antibody-associated demyelination is strongly associated with ON across all age groups and ADEM in children. Patients are highly responsive to steroids, but vulnerable to relapse on steroid reduction and cessation.

Clinical and MRI phenotype of children with MOG antibodies.

OBJECTIVE: To investigate the clinical and magnetic resonance imaging (MRI) features of anti-myelin oligodendrocyte glycoprotein (MOG) antibody-seropositive pediatric demyelinating syndromes. METHODS: Serum samples collected from 74 children with suspected demyelinating disorders whom were being followed at Massachusetts General Hospital were incubated with control green fluorescent protein (GFP)- and MOG-GFP-transfected Jurkat cell clones. The binding ratios were calculated using flow cytometry. Using statistical analyses, we compared the demographic, clinical and radiological features in our seropositive and seronegative patients. RESULTS: We found that 13 out of 74 (17.5%) patients were seropositive for MOG. The MOG-seropositive patients were younger than the seronegative patients (p = 0.049). No single disease category predominated among the seropositive patients, nor was one group more likely to have a polyphasic course. There were two out of four neuromyelitis optica (NMO) patients who had MOG antibodies; both were seronegative for aquaporin -4 (AQP4) antibodies. One had monophasic disease and the other had frequent relapses. There was a bimodal distribution of the MOG-seropositive patients by age at onset, with a distinct younger group (4-8 years) having a high prevalence of encephalopathy and an older group (13-18 years), whom presented almost exclusively with optic neuritis. MRI analysis demonstrated the absence of corpus callosum lesions in the seropositive patients (p = 0.012). The annualized relapse rate (ARR) and the Expanded Disability Status Scale (EDSS) results at 2 years did not differ between the seropositive and seronegative patients. CONCLUSION: MOG antibodies are found across a variety of pediatric demyelinating syndromes having some distinct clinical and MRI features.

Multiple sclerosis, solitary sclerosis or something else?

BACKGROUND: Inflammatory demyelinating diseases of the central nervous system represent a wide spectrum of entities and their classification cannot currently be regarded complete. OBJECTIVE: Our aim is to describe a series of patients presenting with progressive myelopathy associated to a single demyelinating lesion of the spinal cord. METHODS: We identified the patients affected by chronic progressive spinal cord dysfunction related to a single spinal cord lesion not satisfying the diagnostic criteria for any of the currently defined diseases. RESULTS: Seven females and one male were included. The median age at onset of symptoms was 53 years (range 42-68) and the median follow-up was 8 years (range 5-12). Brain and spinal magnetic resonance imaging (MRI) scans detected only one single, circumscribed, T2 hyperintense, non-longitudinally extensive lesion at level of cervico-medullary junction or cervical cord, in the absence of Gadolinium enhancement or swelling. Cerebrospinal fluid (CSF) examination displayed neither oligoclonal bands nor raised IgG index. A response to immunosuppressive agents was observed in some of the patients. Serial control brain and spinal MRI did not reveal accumulation of new lesions. CONCLUSION: New entities or variants should be included among the inflammatory demyelinating diseases of the central nervous system, and their characterization may have relevant prognostic and treatment implications.

Metabotropic glutamate receptor type 1 autoantibody-associated cerebellitis: a primary autoimmune disease?

OBJECTIVES: To report the third case of subacute cerebellar ataxia associated with metabotropic glutamate receptor type 1 autoantibodies (mGluR1-Abs), an uncommon syndrome known to be part of the group of paraneoplastic cerebellar degeneration syndromes linked to antineuronal antibodies and previously reported in only 2 other patients with long-term remission of Hodgkin lymphoma, and to discuss the underlying immunopathogenesis. DESIGN: Case report. SETTING: University hospital. PATIENT: A 50-year-old woman admitted for acute severe isolated static and kinetic cerebellar syndrome. Magnetic resonance imaging of the brain showed diffuse abnormal hyperintensity in the whole cerebellum on fluid-attenuated inversion recovery and diffusion sequences. RESULTS: Results of the biological workup were negative for general inflammation, vitamin deficiency, and bacterial and viral infections. Immunohistochemical analysis of the serum and cerebrospinal fluid of the patient demonstrated staining for Purkinje cell bodies and the molecular layer of the cerebellum. Finally, mGluR1-Abs were detected in serum and cerebrospinal fluid by a cell-based assay. Complete clinical examination, thoracoabdominal-pelvic computed tomography, and whole-body fludeoxyglucose F 18-positron emission tomography failed to show any underlying tumor, including Hodgkin lymphoma. The disease was stabilized after a course of intravenous immunoglobulins and continuous mycophenolate mofetil treatment during a follow-up of 40 months. CONCLUSIONS: Cerebellitis associated with mGluR1-Abs should be considered in the differential diagnosis of patients with subacute cerebellar ataxia. This first case without any tumor found suggests a possible idiopathic autoimmune rather than a paraneoplastic mechanism. In consideration of this possible primitive autoimmune ataxia involving the directly pathogenic mGluR1-Abs, immunoactive therapy should be initiated as early as possible.

Cytokine networks in multiple sclerosis: lost in translation.

PURPOSE OF REVIEW: This review will discuss aspects of cytokine networks in neuroinflammatory diseases and attempt to provide some explanation for our failures and successes in translating preclinical data to benefit patients with multiple sclerosis (MS). We will discuss innate cytokines such as tumor necrosis factor alpha and interferon (IFN) beta and will then go on to cover recent findings on the role of interleukin-23 and the so-called T(H)17 cells and how they are implicated in the pathogenesis of neuroinflammation. RECENT FINDINGS: Even though IFN-beta has been used for the treatment of MS for many years, it is only recently that the mechanistic underpinnings of the IFN-beta-mediated immune modulation was discovered in preclinical models. The timeline is at odds with the idea that preclinical data should shape the design of therapeutic strategies in the clinic. Conversely, the discovery of the so-called T(H)17 cells and their association with neuroinflammation has broken the dogma that IFN-gamma-producing T(H)1 cells have the exclusive capacity to invade and destroy the central nervous system tissue. So why then did a clinical trial targeting the T(H)17-promoting cytokine interleukin-23 fail? SUMMARY: Preclinical studies using the animal models for MS have yielded promising results, but unfortunately the translation into the clinic is often disappointing. The reason for this may be the complex nature of the pathogenesis of autoimmune neuroinflammation, but more often an oversimplified interpretation of preclinical observations appears to hinder our progress.

FTY720 reduces inflammation and promotes functional recovery after spinal cord injury.

A robust and complex inflammatory cascade is known to be a prominent component of secondary injury following spinal cord injury (SCI). Specifically, the concept of trauma-induced autoimmunity has linked the lymphocyte population with neural tissue injury and neurologic deficit. FTY720, a sphingosine receptor modulator that sequesters lymphocytes in secondary lymphoid organs, has been shown to be effective in the treatment of a variety of experimental autoimmune disorders. Accordingly, by reducing lymphocyte infiltration into the spinal cord following SCI, this novel immunomodulator may enhance tissue preservation and functional recovery. In the present study, a moderate to severe contusion SCI was simulated in adult Long-Evans hooded rats. Using flow cytometry we showed that daily FTY720 treatment dramatically reduced T-cell infiltration into the SCI lesion site at 4 and 7 days post-injury, while other inflammatory cell populations were relatively unaltered. To assess functional recovery, three groups of injured animals (treated, vehicle, and injury only) were evaluated weekly for hindlimb recovery. Animals in the treated group consistently exhibited higher functional scores than animals in the control groups after 2 weeks post-injury. This finding was associated with a greater degree of white matter sparing at the lesion epicenter when cords were later sectioned and stained. Furthermore, treated animals were found to exhibit improved bladder function and a reduced incidence of hemorrhagic cystitis compared to control counterparts. Collectively these results demonstrate the neuroprotective potential of FTY720 treatment after experimental SCI.

Transplanted neural stem/progenitor cells generate myelinating oligodendrocytes and Schwann cells in spinal cord demyelination and dysmyelination.

Stem cell therapy is a promising approach for remyelination strategies in demyelinating and traumatic disorders of the spinal cord. Self-renewing neural stem/progenitor cells (NSPCs) reside in the adult mammalian brain and spinal cord. We transplanted NSPCs derived from the adult spinal cord of transgenic rats into two models of focal demyelination and congenital dysmyelination. Focal demyelination was induced by X-irradiation and ethidium bromide injection (X-EB); and dysmyelination was in adult shiverer mutant mice, which lack compact CNS myelin. We examined the differentiation potential and myelinogenic capacity of NSPCs transplanted into the spinal cord. In X-EB lesions, the transplanted cells primarily differentiated along an oligodendrocyte lineage but only some of the oligodendrocytic progeny remyelinated host axons. In this glial-free lesion, NSPCs also differentiated into cells with Schwann-like features based on ultrastructure, expression of Schwann cell markers, and generation of peripheral myelin. In contrast, after transplantation into the spinal cord of adult shiverer mice, the majority of the NSPCs expressed an oligodendrocytic phenotype which myelinated the dysmyelinated CNS axons forming compact myelin, and none had Schwann cell-like features. This is the first study to examine the differentiation and myelinogenic capacity of adult spinal cord stem/progenitors in focal demyelination and dysmyelination of the adult rodent spinal cord. Our findings demonstrate that these NSPCs have the inherent plasticity to differentiate into oligodendrocytes or Schwann-like cells depending on the host environment, and that both cell types are capable of myelinating axons in the demyelinated and dysmyelinated adult spinal cord.

Limbic encephalitis as a precipitating event in adult-onset temporal lobe epilepsy.

OBJECTIVE: Temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) is the most frequent diagnosis in autopsy and surgical epilepsy series. TLE-HS usually starts during childhood or adolescence. There have been few studies of adult-onset disease. We recognized that some adult individuals have evidence of limbic encephalitis (LE), an autoimmune condition of adult life, which we proposed might lead directly to this syndrome. METHODS: We performed a retrospective analysis of history, clinical and paraclinical findings, brain MRI, and outcome of surgical treatment including histopathology (if available) of all patients with TLE-HS presenting to this tertiary center within 6 years of epilepsy onset between 1999 and 2005. RESULTS: Thirty-eight patients were identified, with median age at epilepsy onset of 37.8 years. Eleven patients (29%) were classified as having secondary HS (e.g., after head trauma, febrile seizures). Seven patients (11%) were classified as idiopathic. However, 9 patients (24%) had a diagnosis of definite LE, and another 11 individuals (29%) showed the typical LE pattern of MRI findings with hippocampal swelling evolving into atrophy with continuous FLAIR/T2 signal increase; they were diagnosed as possible LE. Bilateral abnormalities were more frequent in the two LE subgroups (60%) than in the two non-LE subgroups (22%; p = 0.025). Histopathology was performed in one patient with possible LE shortly after disease onset and showed a typical T cell infiltration and loss of hippocampal neurons. CONCLUSIONS: Temporal lobe epilepsy with hippocampal sclerosis can manifest in adult life. Around half the patients have evidence consistent with an autoimmune process. If confirmed, this should have implications for diagnosis, prevention, and treatment.

PD-L1 (B7-H1) regulation in zones of axonal degeneration.

Fibre tract injury evokes recruitment of antigen-presenting- and T cells, but does not cause autoimmune demyelination. This implies that immune tolerance to myelin is actively maintained or readily re-established. Using entorhinal cortex lesion (ECL) to induce axonal degeneration in the hippocampus of adult mice, we studied the induction of B7-H1 (PD-L1) in zones of axonal degeneration. This member of the B7-family has been shown to be expressed on parenchymal cells of various organs, where it strongly down-modulates the activity of T cells. Real-time reverse transcriptase (RT)-PCR revealed low mRNA levels in brain compared to lung and spleen under normal conditions. After ECL, a twofold increase could be observed. Immunocytochemistry revealed astrocytes as source of B7-H1, while immune positive microglia were not detected. Thus, axonal degeneration induces astrocytes to express B7-H1, a potent inhibitor of effector T cells.

White matter alteration in a patient with Graves' disease.

A case of Graves' disease with white matter abnormalities is presented here. The diagnosis as Graves' disease was made when the patient was 5 years old, and a subtotal thyroidectomy was performed when she was 10. Her neurological symptoms began at age 19 with paresthesia of her legs and lower body. Cranial magnetic resonance imaging was normal; thoracic magnetic resonance imaging revealed demyelinating lesions. Intravenous pulse steroid therapy improved her symptoms. Ten months later she described dizziness, lower body paresthesia, and ataxia. Both her cranial and thoracic magnetic resonance imagings revealed demyelinating lesions. After pulse steroid therapy, glatiramer acetate therapy was initiated with diagnosis of an autoimmune multiphasic demyelinating syndrome. Five months later, she presented with right-sided mild optic neuritis followed by rapid spontaneous remission. Antithyroglobulin antibody levels remained normal; antithyroid peroxidase antibody level was high. This presents a rare case of Graves' disease associated with multiphasic demyelinating autoimmune syndrome.

Neurologic manifestations of ulcerative colitis.

Ulcerative colitis (UC) has traditionally been considered to be an inflammatory disease limited to the colonic mucosa. However, since it has been shown that UC is frequently accompanied by various extraintestinal disorders, there is increasing evidence that UC may also manifest in the nervous system. The following review focuses particularly on these possible manifestations of UC, both in the peripheral (PNS), and in the central nervous system (CNS). A systematic literature search according to the MEDLINE database was performed for this purpose. Although a reliable differentiation may clinically not always be possible, three major pathogenic entities can be differentiated: (i) cerebrovascular disease as a consequence of thrombosis and thromboembolism; (ii) systemic and cerebral vasculitis; (iii) probably immune mediated neuropathy and cerebral demyelination. With the exception of thromboembolism and sensorineural hearing loss, evidence for a causal relationship relies merely on single case reports or retrospective case series. Considering the CNS-manifestations, similarities between UC-associated disorders of the white matter and acute disseminated encephalomyelitis (ADEM) are obvious. Epileptic seizures, unspecified encephalopathies and confusional states are most likely epiphenomena that have to be regarded symptomatic rather than as own entities. A prospective study on the neurologic aspects of UC would be very welcome.

T cells contribute to lysophosphatidylcholine-induced macrophage activation and demyelination in the CNS.

We have previously shown that intraspinal microinjection of lysophosphatidylcholine (LPC), a potent demyelinating agent, results in a rapid but brief influx of T cells (between 6 and 12 h). This is accompanied by a robust activation of macrophages/microglia that leads to demyelination by 48 h. In the present study, we examined whether this brief influx of T cells contributes to the activation of macrophages/microglia and demyelination by injecting LPC into the dorsal column white matter of athymic Nude mice that lack T cells. We show that there is a significant reduction in macrophage/microglial activation and myelin clearance after LPC injection in Nude mice as compared with wildtype controls. We also show that there is no difference in the recruitment of hematogenous macrophages into the spinal cord after LPC injection in the two mouse strains. Of the T cell cytokines assessed, there was a marked reduction in the mRNA expression of interleukin-2 (IL-2) in Nude mice compared with wildtype animals. Neutralizing IL-2 with function-blocking antibodies in wildtype animals resulted in a significant decrease in the number of phagocytic macrophages/microglia and a reduction in demyelination induced by LPC. While there may be other defects in Nude mice that might contribute to the effects shown here, these data suggest that the brief influx of T cells in this model of chemically-induced demyelination could play a role in macrophage/microglial activation and demyelination. These results may also have implications for remyelination in this and other types of CNS damage.

Neuropathology of paraneoplastic neuropathy with anti-disialosyl antibody.

We report a paraneoplastic neuropathy with severe motor involvement following sensory-ataxic disturbance. Anti-disialosyl immunoglobulin M (IgM) antibody was detected in the course of malignant lymphoma of diffuse large B-cell type, which usually spares the motor system. Onset was subacute, with relapsing and remitting sensory ataxia, muscle weakness, bulbar palsy, respiratory paralysis, and ophthalmoplegia; only neck rotation was retained in the terminal stage. Autopsy showed no lymphoma cells infiltrating the nervous system. Motor neurons survived in the spinal cord, but mean diameter of the ventral spinal nerve roots was reduced considerably. The gracile fasciculus and the sural nerve were more markedly degenerated than proximal portions. Morphometric study showed that most of the proximal motor and sensory axons did not extend distally. This autopsy report provides further definition of a neuropathy associated with malignant lymphoma and IgM antibodies against disialosyl residues.