Makoto Samukawa

Clinical features of CIDP with LM1-associated antibodies

Background LM1 is the predominant glycolipid in human peripheral nerve myelin and antibodies to LM1 and LM1-containing ganglioside complexes are detected in some patients with chronic inflammatory demyelinating polyneuropathy (CIDP). The clinical features of patients with such antibodies have not yet been investigated. Methods Serum antibodies to LM1, a mixture of GM1 and LM1 (GM1/LM1), and that of GD1b and LM1 (GD1b/LM1) were examined in 75 consecutive patients with CIDP. The clinical features of the CIDP patients with such antibodies in the present series and those in the previous reports were investigated and compared with those of antibody-negative patients. Results Of the 75 patients with CIDP, two had antibodies to LM1, three had anti-GM1/LM1 complex antibody, one had anti-GD1b/LM1 complex antibody and two had antibodies to both the GM1/LM1 and GD1b/LM1 complexes. Patients with the LM1-associated antibodies did not have cranial nerve deficits (p<0.05) and exhibited ataxia more frequently than the antibody-negative patients (p<0.01). Conclusion In humans, LM1 is contained more in the dorsal root than in the cranial nerves. The clinical features of CIDP patients with antibodies to LM1 and LM1-containing complexes may be associated with the distribution of the LM1 antigen. LM1-associated antibodies are possible markers for a subclass of CIDP.

A Case of Severe Neurotoxicity Associated With Exposure to 1-Bromopropane, an Alternative to Ozone-Depleting or Global-Warming Solvents

Health hazard alerts to 1-bromopropane, an alternative to ozone layer-damaging organic solvents, have been issued by some countries. Herein, we report a new case of 1-bromopropane-induced neurotoxicity. A 43-year-old male industrial worker developed muscle weakness, pain, numbness, and gait disturbance. Neurological examination indicated sensory ataxic neuropathy associated with mild impairment of upper motor neurons. He had used 1-bromopropane as a cleaning agent for metal parts at his workplace without appropriate protection. The serum bromide level was elevated at the onset of clinical manifestations. Histopathologic examination of sural nerve biopsy showed axonal damage. Under the tentative diagnosis of 1-bromopropane toxicity, he was kept away from exposure to the solvent. This resulted in gradual improvement of symptoms, recovery of motor function, and resolution of sensory deficits. The diagnosis of 1-bromopropane neurotoxicity in this case was based on details of the work environment, the clinical course, and laboratory and pathologic findings. To our knowledge, this is the first report that describes nerve biopsy findings in a human case.

Effector Regulatory T Cells Reflect the Equilibrium between Antitumor Immunity and Autoimmunity in Adult T-cell Leukemia.

Anti-CCR4 treatment of ATL destroys leukemic and normal Tregs, which can lead to autoimmunity. Only leukemic Tregs expressed CADM1, distinguishing the two populations. Treg depletion was associated with autoimmunity and Treg reemergence with relapse of ATL. The regulatory T cells (Treg) with the most potent immunosuppressive activity are the effector Tregs (eTreg) with a CD45RA–Foxp3++CCR4+ phenotype. Adult T-cell leukemia (ATL) cells often share the Treg phenotype and also express CCR4. Although mogamulizumab, a monoclonal antibody to CCR4, shows marked antitumor effects against ATL and peripheral T-cell lymphoma, concerns have been raised that it may induce severe autoimmune immunopathology by depleting eTregs. Here, we present case reports for two patients with ATL who responded to mogamulizumab but developed a severe skin rash and autoimmune brainstem encephalitis. Deep sequencing of the T-cell receptor revealed that ATL cells and naturally occurring Tregs within the cell population with a Treg phenotype can be clearly distinguished according to CADM1 expression. The onset of skin rash and brainstem encephalitis was coincident with eTreg depletion from the peripheral blood, whereas ATL relapses were coincident with eTreg recovery. These results imply that eTreg numbers in the peripheral blood sensitively reflect the equilibrium between antitumor immunity and autoimmunity, and that mogamulizumab might suppress ATL until the eTreg population recovers. Close monitoring of eTreg numbers is crucial if we are to provide immunomodulatory treatments that target malignancy without severe adverse events. Cancer Immunol Res; 4(8); 644–9. ©2016 AACR.

Refractory acute disseminated encephalomyelitis with anti-galactocerebroside antibody

Acute disseminated encephalomyelitis causes multifocal demyelination in the central nerve system. Although this disease generally responds well to steroid therapy, it is occasionally steroid-resistant, leading to poor outcomes. Serological markers of prognosis are currently unavailable. We measured anti-glycolipid antibodies in 25 consecutive patients with acute disseminated encephalomyelitis, and found that four patients were positive for anti-galactocerebroside antibodies. All four patients had a poor response to steroids. We summarize clinical information on these four patients and three similar patients reported previously. This is the first report to describe concomitant involvement of the central nerve system and peripheral nervous system in anti-galactocerebroside antibody-associated acute disseminated encephalomyelitis, consistent with the location of galactocerebroside, and to document a dramatic response to repeated intravenous immunoglobulin therapy after unsuccessful steroid treatment in one patient.

Characterization of the neurological diseases associated with Mycoplasma pneumoniae infection and anti-glycolipid antibodies

Mycoplasma pneumoniae infection often causes various neurological complications of both the central nervous system (CNS) and the peripheral nervous system. We retrospectively investigated the IgM and IgG antibodies to nine glycolipids [GM1, GM2, GM3, GD1a, GD1b, GD3, GT1b, GQ1b, and Gal-C (galactocerebroside)] and clinical features in neurological diseases associated with M. pneumoniae infection diagnosed in multiple hospitals throughout Japan between September 2010 and March 2012. Of the 46 patients with neurological diseases associated with M. pneumoniae infection, 27 were diagnosed with Guillain–Barré syndrome (GBS), 2 with Fisher syndrome (FS), 16 with CNS diseases, and 1 with both GBS and CNS disease. Anti-Gal-C IgM and IgG antibodies were most frequently detected (23/46, 50%). Patients with CNS diseases were younger than patients with GBS or FS, and IgM antibodies to Gal-C were more frequently detected in the patients with CNS diseases (41%) than in those with GBS or FS (13%). Of the nine patients who were positive for anti-Gal-C IgM antibody but lacked IgG antibody, we found the class-switch of anti-Gal-C antibody from IgM to IgG in two patients. The IgG antibodies appeared during their recovery phase, and the IgG belonged to the IgG1 subclass. Anti-Gal-C antibodies are closely associated with neurological diseases after M. pneumoniae infection. Particularly, anti-Gal-C IgM antibody is more frequently detected in younger patients affected with CNS involvement. The class-switch from IgM to IgG sometimes occurs in anti-Gal-C antibodies.

Details of Treatment-Related Difficulties in Men with Anti-N-Methyl-d-Aspartate Receptor Encephalitis

Anti-N-methyl-d-aspartate receptor (anti-NMDAR) antibody-associated encephalitis is an immunologic disease characterized by a female preponderance. Males are infrequently affected. The clinical symptoms of affected boys as well as girls have been summarized, and they have some clinical features distinct from those of adults. However, the characteristics of men have been described in only a few reports. We describe in detail four men with anti-NMDAR encephalitis who presented with several clinical features that complicated disease management and recovery, including venous thrombosis, bilateral hippocampal involvement, hypersexuality, and joint contracture. We also report the first detailed clinical information about a male patient who died of this disease. In addition, we summarize the clinical characteristics of five patients previously reported by others.

Serological study using glycoarray for detecting antibodies to glycolipids and glycolipid complexes in immune-mediated neuropathies

We performed a serological investigation using glycoarray in Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and multifocal motor neuropathy (MMN). Antibodies to 10 glycolipids and 45 glycolipid complexes were tested. Anti-GM1/sulfatide and anti-GA1/sulfatide IgG antibodies were common in GBS (20.0% and 19.0%, respectively). Anti-GQ1b/sulfatide IgG antibody was detected in 14.0% of GBS patients. IgG antibodies to antigens containing GQ1b were significantly correlated with ophthalmoplegia in GBS (p<0.01). IgM antibodies to antigens containing GM1 or GalNAc-GD1a were in 50% and 37.5% of MMN patients, respectively. Glycoarray is efficient for detecting antibodies against numerous glycolipid complexes in immune-mediated neuropathies.

Binding specificity of anti-HNK-1 IgM M-protein in anti-MAG neuropathy: Possible clinical relevance

Anti-myelin-associated-glycoprotein (MAG) neuropathy is an intractable autoimmune polyneuropathy. The antigenic region of MAG is the human natural killer-1 (HNK-1) carbohydrate. We and others previously suggested that the extension of antibody reactivities to HNK-1-bearing proteins other than MAG was associated with treatment resistance, without statistical analyses. In this study, we established an ELISA method with recombinant proteins to test binding specificities of currently available monoclonal antibodies to MAG and another HNK-1-bearing protein, phosphacan. Using this system, we found the distinct binding specificities of anti-MAG antibody in 19 patients with anti-MAG neuropathy. Their clinical relevance was then determined retrospectively with the adjusted 10-points INCAT disability score (0 = normal and 10 = highly disable). The results showed that strong reactivities of anti-MAG antibodies to phosphacan were significantly associated with treatment resistance or progressive clinical courses, indicating a possible clinical relevance of the binding specificities.

A case of anti-N-methyl-D-aspartate receptor encephalitis with systemic sclerosis

Sir, Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is characterized by the presence of antibodies against NR1–NR2 heteromers of the NMDAR (anti-NMDAR antibodies) with ovarian teratoma [1]. However, recently, it has become clear that anti-NMDAR encephalitis is not always paraneoplastic [2]. We present a female patient affected with anti-NMDAR encephalitis and systemic sclerosis (SSc), the disease activity of which synchronized with each other. A 70-year-old female patient had Raynaud s phenomenon, weight loss, easy fatigability, muscle weakness, and skin sclerosis. Six months later, she presented with cognitive impairment and gait disturbance. Physical examination showed skin sclerosis and ulcers on the hands, face, and feet. Neurological examination revealed dementia (15/30 in the MiniMental State Examination), resting tremor, ataxia, rigidity, and muscle weakness in the extremities. Pathological reflexes were bilaterally positive. Brain magnetic resonance imaging (MRI) showed high intensities in bilateral basal ganglia and thalamus on fluid-attenuated inversion recovery (FLAIR) images (Fig. 1). Brain magnetic resonance angiography showed normal. Initial cerebrospinal fluid (CSF) examination showed normal cell count, elevated total protein (112 mg/dl) and IL-6 (5.8 pg/ml). Oligoclonal IgG Bands were negative. Chest computed tomography (CT) showed mild interstitial pneumonitis (Fig. 1). Serological analysis showed increased serum antinuclear antibody titer (1:80 with diffuse speckled pattern). Elevation of tumor markers (CEA, NSE, Pro-GRP, and AFP) or paraneoplastic antineuronal antibodies were not revealed. Anti-NMDAR anti-

Electrophysiological assessment of Guillain-Barré syndrome with both Gal-C and ganglioside antibodies; tendency for demyelinating type

Whether patients who have GBS with antibodies to galactocerebroside (Gal-C) and gangliosides (Gal-C-GS-GBS) more often have demyelinating or axonal neuropathy remains controversial. We assessed the electrophysiological data from 16 patients with Gal-C-GS-GBS based on the two established criteria to clarify this issue. In this largest cohort of Gal-C-GS-GBS, eight patients had demyelinating neuropathy and none exhibited axonal neuropathy on either criterion. These data indicated that antibodies to Gal-C, a myelin antigen, might predominantly be associated with demyelinating neuropathy, even in the presence of concomitant antibodies to gangliosides.