Anti-aquaporin 4 antibody in selected Japanese multiple sclerosis patients with long spinal cord lesions.

Multiple sclerosis (MS) in Asian populations is often characterized by the selective involvement of the optic nerve (ON) and spinal cord (SP) (OSMS) in contrast to classic MS (CMS), where frequent lesions are observed in the cerebrum, cerebellum or brainstem. In Western countries, inflammatory demyelinating disease preferentially involving the ON and SP is called neuromyelitis optica (NMO). Recently, Lennon et al. discovered that NMO-IgG, shown to bind to aquaporin 4 (AQP4), could be a specific marker of NMO and also of Japanese OSMS whose clinical features were identical to NMO having long spinal cord lesions extending over three vertebral segments (LCL). To examine this antibody in larger populations of Japanese OSMS patients in order to know its epidemiological and clinical spectra, we established an immunohistochemical detection system for the anti-AQP4 antibody (AQP4-Ab) using the AQP4-transfected human embryonic kidney cell line (HEK-293) and confirmed AQP4-Ab positivity together with the immunohistochemical staining pattern of NMO-IgG in approximately 60% of Japanese OSMS patients with LCL. Patients with OSMS without LCL and those with CMS were negative for this antibody. Our results accorded with those of Lennon et al. suggest that Japanese OSMS with LCL may have an underlying pathogenesis in common with NMO.

Beta-synuclein gene alterations in dementia with Lewy bodies.

OBJECTIVE: To determine whether mutations in the genes for alpha-synuclein or beta-synuclein are responsible for dementia with Lewy bodies (DLB), a disorder closely related to Parkinson disease (PD). METHODS: The authors ascertained 33 sporadic cases of DLB and 10 kindreds segregating DLB. DNA samples from the 43 index cases were screened for alterations in the genes for alpha-synuclein and beta-synuclein, as alpha-synuclein alterations cause PD and beta-synuclein may modulate alpha-synuclein aggregation and neurotoxicity. RESULTS: Two amino acid alterations were identified in unrelated DLB index cases: a valine to methionine substitution at codon 70 (V70M) and a proline to histidine substitution at codon 123 (P123H), both in the beta-synuclein gene. These amino acid substitutions occur at conserved residues in highly conserved regions of the beta-synuclein protein. Screening of at least 660 chromosomes from control subjects matched to the patients' population groups failed to identify another V70M or P123H allele. Cosegregation analysis of an extended pedigree segregating the P123H beta-synuclein alteration suggested that it is a dominant trait with reduced penetrance or a risk factor polymorphism. Histopathology and immunohistochemistry analysis of index case brain sections revealed widespread Lewy body pathology and alpha-synuclein aggregation without evidence of beta-synuclein aggregation. CONCLUSION: Mutations in the beta-synuclein gene may predispose to DLB.

Failure to detect cytotoxic T cell activity against recombinant Yo protein using autologous dendritic cells as the target in a patient with paraneoplastic cerebellar degeneration and anti-Yo antibody.

Paraneoplastic neurological syndromes are believed to be autoimmune neuronal degenerations that develop in some patients with systemic cancer. Although a high titer of anti-Yo antibody has been found in the sera and cerebrospinal fluid of patients with paraneoplastic cerebellar degeneration (PCD), the role of anti-Yo antibody in Purkinje cell loss has not been shown. Previously we found that all of nine Japanese patients with PCD who harbored anti-Yo antibody had HLA A24. In this present study we have examined cytotoxic T cell (CTL) activity against recombinant Yo protein in peripheral blood of a patient with PCD and anti-Yo antibody using autologous dendritic cells as the target. We did not detect CTL activity against Yo protein, though, this study does not exclude the possibility of the involvement of CTL in the development of PCD.

[A patient with an ACTH-releasing thymic carcinoid tumor presenting with proximal muscle weakness].

We report a 36-year-old man with proximal dominant muscle weakness, thymic tumor, diabetes mellitus, hypokalemia, and increased levels of plasma ACTH and cortisol. The diagnosis of carcinoid tumor was made on the basis of pathological findings in the biopsied specimen of the thymic tumor. The proximal muscle weakness was considered to be due to steroid myopathy resulting from the overproduction of cortisol from the adrenal glands induced by the ectopic ACTH secreted by the thymic carcinoid tumor. Although thymoma in frequently associated with myasthenia gravis, we should also consider carcinoid tumors in patients with a thymic tumor presenting with a proximal muscle weakness.

Progressive atrophy of cerebellum and brainstem as a function of age and the size of the expanded CAG repeats in the MJD1 gene in Machado-Joseph disease.

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disease characterized by cerebellar ataxia associated to varying degrees with pyramidal signs, extrapyramidal signs, or peripheral amyotrophy. It is caused by unstable expansion of the CAG repeat in the MJD1 gene on chromosome 14q32.1. To determine how the neurodegenerative process in the central nervous system of patients with MJD correlates with the size of expanded CAG repeats in the MJD1 gene and other factors, we performed detailed quantitative analyses of findings of magnetic resonance imaging of the central nervous system of 21 patients with MJD of various ages and with various sizes of expanded CAG repeats. We found that atrophy of the brainstem and cerebellar vermis in MJD patients is closely correlated not only with the size of expanded CAG repeat in the MJD1 gene but also with patient age, which suggests that the neurodegenerative process in MJD is regulated by the size of expanded CAG repeats as well as by the patient age.

Cytotoxic T cells react with recombinant Yo protein from a patient with paraneoplastic cerebellar degeneration and anti-Yo antibody.

Antibodies against autologous tumor cells and neurons are found in the sera or cerebrospinal fluid of patients with paraneoplastic neurological syndromes. Attempts to produce animal models by passive transfer or active immunization, however, have failed, and there is no direct evidence that antibodies cause neuronal damage. Previously, we found that patients with paraneoplastic cerebellar degeneration (PCD) and anti-Yo antibody tested had HLA A24. We now have studied cytotoxic T cell activity in peripheral blood that reacts with recombinant Yo protein when autologous dendritic cells are used as the target. Results suggest that cytotoxic T cells are involved in Purkinje cell loss in PCD.

Corticobasal degeneration with neither argyrophilic inclusions nor tau abnormalities: a new subgroup?

In corticobasal degeneration (CBD), cerebral cortical neuronal loss with achromasia and degeneration of the subcortical nuclei, particularly the substantia nigra, are common. Recent studies have suggested that the occurrence of argyrophilic nigral inclusions, resembling the neurofibrillary tangles found in progressive supranuclear palsy, and widespread tau abnormalities may be features of CBD. We studied brain tissues from two patients in whom CBD was suspected clinically. From the distribution of their cortical and subcortical lesions, the patients were diagnosed as having CBD. However, Gallyas/tau-positive neuronal and glial structures were not found, which suggests there may be a subgroup of CBD with neither argyrophilic inclusions nor tau abnormalities.

[MRI findings of olivopontocerebellar atrophy and Machado-Joseph disease--diagnostic value of transverse pontine fibers].

Olivopontocerebellar atrophy (OPCA) and Machado-Hoseph disease (MJD) occasionally show similar clinical signs and symptoms, which makes differential diagnosis of OPCA and MJD difficult. In 1990, Savoiardo et al. reported that the transverse pontine fibers of OPCA patients had high signal intensity on T2 weighted MR images. To determine if the high signal intensity of the transverse pontine fibers is useful for the differential diagnosis of OPCA and MJD, we examined this abnormal intensity in patients diagnosed as OPCA or MJD. We observed the high intensity of transverse pontine fibers in all of the 18 OPCA patients. This finding, however, was not observed in any of the patients with the MJD. The high signal intensity of the transverse pontine fibers in T2 weighted images is characteristic of OPCA patients. Furthermore the atrophy of pontine tegmentum is characteristic of patients with MJD. These findings correlate well with pathological findings of OPCA and MJD, indicating the usefulness of these MRI findings for the differential diagnosis of OPCA and MJD.

[A case of isocyanate-induced hypersensitivity pneumonitis and a compression-air mask thought to be effective in its prevention].

A 41-year-old paint sprayer, who had worked with polyurethane paint since the spring of 1989, developed exertional dyspnea and dry cough and entered hospital on December 4, 1989. Plain chest X-ray film and a computed tomogram of the lung revealed diffuse micronodular shadows in both lower lung fields. DLco was shown to be significantly decreased in a pulmonary function test. A sample of bronchoalveolar lavage fluid showed increased T lymphocytes and a decreased CD4/8 ratio. A lung biopsy specimen revealed alveolitis, but neither Masson body nor granulomas were seen. Serum antibody specific to TDI-HSA was detected, and an environmental provocation test was positive. From these results, the patient was diagnosed as having isocyanate-induced hypersensitivity pneumonitis. We advised him to wear a compression-air mask when he worked, because he did not want to quit his job. Respiratory symptoms have not been seen since then, but careful observation was thought to be necessary. The involvement of type III humoral and type IV cellular immunity was suspected in this case.