Characterization of the neurological diseases associated with <Emphasis Type="Italic">Mycoplasma pneumoniae</Emphasis> 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.     

Anti-Gal-C antibodies in GBS subsequent to mycoplasma infection: evidence of molecular mimicry

The authors previously reported the presence of antibody against galactocerebroside (Gal-C) in sera from patients with Guillain-Barré syndrome subsequent to Mycoplasma pneumoniae infection. Anti-Gal-C antibody activities in these sera were inhibited specifically by the M. pneumoniae reagent. A rabbit anti-Gal-C antibody recognized several glycolipids in M. pneumoniae. These data show that a Gal-C-like structure is present in M. pneumoniae, indicative of molecular mimicry between a major myelin glycolipid, Gal-C, and M. pneumoniae.     

Guillain-Barré syndrome and optic neuritis after Mycoplasma pneumoniae infection

We report the case of a 12-year-old girl who developed Guillain-Barré syndrome (GBS) and optic neuritis (ON) following Mycoplasma pneumoniae infection.Her symptoms, including bilateral vision impairment and tingling in her hands and right foot, were resolved after methylprednisolone pulse therapy. Serum anti-galactocerebroside (Gal-C) IgM antibodies were detected in our patient.This is the first report of a child with GBS and ON associated with M. pneumoniae infection.     

Mycoplasma antibody in guillain-barré syndrome and other neurological disorders

Counterimmunoelectrophoresis (CIEP) was used to determine precipitating antibodies to Mycoplasma pneumoniae retrospectively in sera from 100 patients with Guillain-Barré syndrome (GBS), 125 medical and neurological controls, and 40 normal individuals. Sera from 7 patients produced precipitin lines. These positive cases included 5 patients with GBS, 1 with acute cerebellar ataxia, and 1 with acute disseminated encephalomyelitis. A complement-fixation test performed with the same antigen showed titers to M. pneumoniae of 1:512 or greater in these 7 sera. In contrast, sera from other patient controls and normal individuals were negative by CIEP and had only low mycoplasma complement-fixation antibody titers. No distinguishing clinical features separated the 5 seropositive GBS patients from the whole group except for their young age, which parallels that for human mycoplasma infection in general. Additional laboratory findings consistent with acute mycoplasma infection were demonstrated in 6 of the 7 seropositive patients.     

Severe childhood Guillain‐Barré syndrome associated with Mycoplasma pneumoniae infection: a case series

We report seven children with recent Mycoplasma pneumoniae infection and severe Guillain‐Barré syndrome (GBS) that presented to two European medical centres from 1992 to 2012. Severe GBS was defined as the occurrence of respiratory failure, central nervous system (CNS) involvement, or death. Five children had GBS, one Bickerstaff brain stem encephalitis (BBE), and one acute‐onset chronic inflammatory demyelinating polyneuropathy (A‐CIDP). The five patients with severe GBS were derived from an original cohort of 66 children with GBS. In this cohort, 17 children (26%) had a severe form of GBS and 47% of patients with M. pneumoniae infection presented with severe GBS. Of the seven patients in this case series, five were mechanically ventilated and four had CNS involvement (two were comatose). Most patients presented with non‐specific clinical symptoms (nuchal rigidity and ataxia) and showed a rapidly progressive disease course (71%). Antibodies against M. pneumoniae were detected in all patients and were found to be intrathecally synthesised in two cases (GBS and BBE), which proves intrathecal infection. One patient died and only two patients recovered completely. These cases illustrate that M. pneumoniae infection in children can be followed by severe and complicated forms of GBS. Non‐specific clinical features of GBS in such patients may predispose a potentially life‐threatening delay in diagnosis.     

Preceding infections and anti-ganglioside antibody profiles assessed by a dot immunoassay in 306 French Guillain–Barré syndrome patients

We describe by an in-house dot immunoassay, specific anti-ganglioside and sulfatide antibodies, by comparing the results from a large group of 134 infected French GBS patients and those from 172 noninfected French GBS and 142 control groups. A recent infection was identified in 134/306 (43.8%) GBS patients: Campylobacter jejuni (24.6%) was the most common agent, followed by cytomegalovirus (12.4%), Mycoplasma pneumoniae (3.2%) and Epstein-Barr virus (1.3%). Anti-ganglioside antibodies were detected in 97/306 (31.7%) of total GBS patients, 82/134 (61.2%) of GBS patients with a recent identified infection and 15/172 (8.7%) of the patients without identified infection. According to the specificities and antibody classes, four specific IgG antibody profiles were individualised against the two major GM1 and GD1a gangliosides in motor axonal C. jejuni-associated GBS variants, against GQ1b and disialylated gangliosides in Miller Fisher syndrome and its variants. One specific IgM profile against GM2 was found in 16/38 (42%) of severe sensory demyelinating CMV-associated GBS and in 8/17 (47%) of subjects with recent CMV infection with no neurological disease. IgG or IgM antibodies to GM1 were found in 5/10 M. pneumoniae-infected patients. IgM antibodies to GM1 were observed in the control groups, 15% of the 74 patients with amyotrophic lateral sclerosis, 19% of the 51 patients with chronic inflammatory demyelinating polyneuropathy, and 9% of the 21 healthy control subjects. The fine specificity of the four IgG antibody profiles and the IgM anti-GM2 profile is closely related to the nature of the preceding infections and the pattern of clinical features.     

Effector mechanisms of PNS demyelination in Gal-C induced-EAN

Myelin in PNS is multi-layered membranes formed by Schwann cells, and surrounds axon. Destruction of myelin sheath results in demyelination and disturbance of nerve conduction. In PNS, Charcot-Marie-Tooth disease, certain lipidoses, Guillain-Barré syndrome, lead poisoning, compression and some metabolic neuropathies can produce demyelination. In these diseases, GBS is thought to be resulted from abnormalities of immune mechanism. Recently, autoantibodies against Gal-C, P2 and GM1, and complement fixing antibodies against PNS myelin are found in some of GBS patient sera. Here, I present studies on effector mechanism of PNS demyelination using models produced by application of Galactocerebroside (Gal-C) antibodies to PNS. Mainly, three types of effector mechanisms are involved in Gal-C antibody-induced demyelination. In abundance of antibodies, complement-mediated demyelination is at work. When complements are absent, antibody dependent macrophage-mediated demyelination can be involved. Thirdly, myelin once damaged by oxidants and etc can be opsonized by antibodies and C3b, and phagocytized by macrophages. These processes may be operating in such diseases like GBS and CIDP.     

Immune responses to myelin antigens in Guillain-Barré syndrome

Antibodies to nerve antigens were sought in the sera of 17 patients with acute Guillain-Barré syndrome (GBS), 11 with chronic relapsing demyelinating poly-radiculoneuropathy (CRP), 20 with other neuropathies (ON), 15 with other neurological diseases (OND) and 19 normal subjects. Complement-fixing antibodies to a suspension of human peripheral nerve tissue were identified in only 2 patients with GBS and 1 with chronic progressive neuropathy. Five GBS sera gave complement fixation reactions with rabbit sciatic nerve. The sera were also tested for galactocerebroside (Gal-C) binding activity using a solid phase assay. The range of values in all groups was the same, although the mean values for patients with GBS, ON and OND were higher than those of normal subjects. In a radioimmunoassay for antibodies to bovine P2 slightly more radiolabelled antigen was precipitated by the GBS group of sera than by sera from the other groups, but only one serum from the GBS and another from the CRP patients precipitated more than 10% of the label. Addition of bovine P2 to cultures of peripheral blood mononuclear cells from 11 patients with GBS did not cause significant stimulation. Immunoassay for antibody to myelin basic protein (MBP) showed an increased proportion of sera with low binding activity in the GBS and CRP groups. The results suggest that humoral immune responses to potentially neuritogenic antigens are found with marginally increased frequency in patients with GBS and CRP.     

Immunoglobulin KM allotypes are associated with the prevalence of autoantibodies to GD1a ganglioside, but not with susceptibility to the disease, in Japanese patients with Guillain–Barré syndrome

Guillain–Barré syndrome (GBS), an autoimmune disease of the peripheral nervous system, is associated with antecedent Campylobacter jejuni infection. GM and KM allotypes—genetic markers of immunoglobulin γ and κ chains, respectively—are implicated in the etiopathogenesis of several autoimmune diseases. To determine if GM/KM phenotypes are associated with GBS and influence antibody responses to C. jejuni and to GM1 and GD1a gangliosides, 72 Japanese GBS patients and 73 controls were allotyped for several GM and KM markers. Sera from patients were characterized for antibodies to C. jejuni, GM1, and GD1a. The distribution of KM phenotypes was significantly different in patients with anti-GD1a ganglioside antibodies from those who lacked these antibodies (P=0.029). No other significant associations were found. These results suggest that KM allotypes are not risk factors for developing GBS, but contribute significantly to the generation of autoimmune responses to GD1a ganglioside in patients with this disease.     

The Magnetic Resonance Image Appearance of Mycoplasma neumoniae Encephalopathy

Although the pathogenesis is unknown, the neurological manifestations of Mycoplasma pneumoniae are protean. Direct nervous system invasion by the organism and an autoimmune demyelination have been implicated. The patient reported here developed M. pneumoniae encephalopathy wherein the clinical and imaging data documented the development and resolution of a central nervous system lesion consistent with inflammation. The images and clinical course suggest a delayed hypersensitivity or autoimmune process similar to that of acute disseminated encephalomyelitis.     

A case with anti-galactocerebroside antibody-positive Mycoplasma pneumoniae meningoencephalitis presenting secondary hypersomnia

Galactocerebroside (Gal-C) is a major myelin component in the central nervous system. The anti-Gal-C antibody induced by mycoplasma infection may therefore be involved in the pathogenic mechanisms of mycoplasma-associated encephalitis. Here we report an adult case of mycoplasma encephalitis developing excessive daytime sleepiness. Brain MRI suggested that hypothalamic involvement was compatible with hypersomnia. This finding was corroborated by decreased hypocretin-1 in cerebrospinal fluid (CSF) and the manifestation of diabetes insipidus. Screening for anti-glycolipid antibody profiles showed the selective increase of serum anti-Gal-C antibody. After treatment with minocyclin, the patient’s daytime sleepiness was markedly improved and the CSF hypocretin-1 level became almost normal, as well. It is known that CSF hypocretin-1 is decreased in Guillain-Barré syndrome mediated by anti-glycolipid antibody, suggesting a possible mechanistic link between anti-glycolipid antibodies and hypothalamic involvement. The present case further emphasizes the broad spectrum of neurological complications after mycoplasma infection.     

Immunoadsorption therapy for a child with Guillain-Barre syndrome subsequent to Mycoplasma infection: a case study

We report an 11-year-old boy with apparently the motor axonal form of Guillain-Barre syndrome (GBS) who presented with severe paralysis and respiratory insufficiency by the 3rd day from onsets of symptoms. His serum anti-Mycoplasma pneumoniae and anti-Galactocerebroside (Gal-C) IgM antibody were significantly elevated. Magnetic resonance imaging, following contrast injection, showed enhancement of the cauda equina. The patient responded quickly and dramatically to immunoadsorption therapy using a tryptophan-immobilized column, with recovery of respiratory failure and muscle strength, dominantly in the left extremities. Immunoadsorption therapy should be considered for patients with anti Gal-C antibody-associated GBS.     

A case of pharyngeal-cervical-brachial variant of Guillain-Barré syndrome with positive anti-galactocerebroside (Gal-C) IgM antibody]

A 49-year-old man presented with hoarseness, dysphagia, muscle atrophy and weakness of deltoid, trapezius, sternocleidomastoid, rhomboid, anterior serratus, infraspinatus and supraspinatus. Anti-Gal-C IgM antibody was positive in the serum. The other antiganglioside antibodies (GM1, GM2, GM3, GD1a, GD1b, GD3, GT1a, GT1b, GQ1b, GA1, GalNAc-GD1a, GM1b) were negative. Patient contracted pneumonia but whether it was due to mycoplasma was not evident. Plasmapheresis improved his clinical state including a decrease of the antibody. This case was diagnosed pharyngeal-cervical-brachial variant of Guillain-Barré syndrome, and anti-Gal-C antibody seemed to be correlated with the pathogenesis of this syndrome. Gal-C is a major glycolipid of myelin and the cell membrane of the myelin-forming cell (oligodendrocytes and Schwann cells) and is free of specific localization and distribution. The mechanism how the anti-Gal-C IgM antibody induced bulbar paralysis and the symptoms localizing neck and upper limbs remains to be known.     

Increased levels of activated T-cells and reduced levels of CD4/CD25+ cells in peripheral blood of Guillain-Barré syndrome patients compared to controls

Guillain-Barré syndrome (GBS) is a severe, self-limiting, autoimmune motor neuropathy. This study was performed to investigate the numbers of activated T-cells and regulatory T-cells, and CD95 and bcl-2 expression in GBS patients compared to controls. The percentage of cells expressing CD69 (activated T-cells) was increased in the blood of both patients with GBS and those with other neuropathies compared to healthy controls. GBS patients displayed significant decreases in the percentage of T-lymphocytes (CD3) and CD4/CD25+ cells (T regulatory cells) compared to patients with other neuropathies and a reduction in the percentage of cytotoxic/suppressor T-lymphocytes (CD8) compared to healthy controls. CD95 expression was reduced in GBS compared to patients with other neuropathies and expression of Bcl-2 was increased in GBS compared to healthy controls. We therefore suggest that in GBS there are increased activated T-cells and disturbances in regulatory T-cells and T-cell apoptosis.     

Clinical characteristics and outcomes of patients with Guillain–Barré and acquired CNS demyelinating overlap syndrome: a cohort study based on a literature review

Abstract

Background:

Some patients with Guillain–Barré syndrome (GBS) also have acquired demyelination of the central nervous system (CNS) (i.e. acquired demyelinating syndrome, ADS). Often, the overlap of GBS and ADS is overlooked. Therefore, we evaluated case reports of GBS/ADS overlap syndrome.

Methods:

We mainly performed website-based research based on articles in cases presented with GBS/ADS overlap syndrome. A total of 66 cases were included. Clinical and prognosis data were analyzed.

Results:

A total of 85% of patients with simultaneous or consecutive occurrence of GBS and ADS were identified within 4 weeks of the initial diagnosis. Transverse myelitis (TM) (32%) was the most common ADS found in GBS/ADS. Patients with Miller Fisher syndrome (MFS)/ADS overlap syndrome had greater female predominance, mean age, frequency of onset at the same time period, or within a short period, and percentage of sole involvement of the subtentorial region. The outcome was favorable based on the functional status in 74% of patients. The sensory level (OR = 0·182, 95% CI = 0·055–0·598; P = 0·005) was the best predictor of a poor outcome, while visual deficit (OR = 4·667, 95% CI = 1·187–18·352; P = 0·027) predicted a favorable outcome.

Conclusion:

The ADS in GBS are diverse, CNS demyelinating may occur at any time, but early in the GBS course (and vice versa). MFS/ADS overlap syndromes is more common. The prognosis is generally good, but patients with sensory level deficit are likely to have a poor prognosis. The features of MFS/other CIS may better reflect involvement of the brainstem in MFS itself, rather than ADS in autoimmune peripheral neuropathies.     

Autoantibodies to peripheral nerve glycosphingolipids SPG, SLPG, and SGPG in Guillain–Barré syndrome and chronic inflammatory demyelinating polyneuropathy

Unlike CNS myelin, human peripheral nerve myelin has the acidic glycosphingolipids sialosyl paragloboside (SPG), sialosyl lactosaminyl paragloboside (SLPG), and sulfated glucuronyl paragloboside(SGPG). To elucidate the pathogenesis of Guillain–Barré syndrome (GBS) and chronic inflammatory demyelinating neuropathy (CIDP), we investigated the autoantibodies to peripheral nerve molecules in patients with these diseases and compared the frequency of the autoantibodies with that of autoantibody to GM1 which is present in both the CNS and PNS. The report of Sheikh et al. (Ann. Neurol. 1995; 38: 350) that Campylobacter jejuni bears the SGPG epitope led us to study whether sera from patients with GBS subsequent to C. jejuni enteritis have anti-SGPG antibody; but, high anti-SGPG antibody titers were not found in the GBS patients from whom C. jejuni was isolated. Although the frequency of the anti-SPG, anti-SLPG, and anti-SGPG antibodies were lower than that of the anti-GM1 antibody in GBS, 5 patients with demyelinating GBS had high IgG anti-SPG antibody titers. IgG anti-SPG antibody may function in the development of demyelinating GBS. We found that 6 CIDP patients had elevated IgM anti-SGPG antibody titers. Immunoelectrophoresis failed to detect IgM M-protein in 3 of the patients. IgM anti-SGPG antibody could be a diagnostic marker for a subgroup of CIDP with or without paraprotein.     

Expression of antigen processing and presenting molecules by Schwann cells in inflammatory neuropathies

Schwann cells are the myelinating glia cells of the peripheral nervous system (PNS) and can become targets of an autoimmune response in inflammatory neuropathies like the Guillain‐Barré syndrome (GBS). Professional antigen presenting cells (APCs) are known to promote autoimmune responses in target tissues by presenting self‐antigens. Other cell types could participate in local autoimmune responses by acting as nonprofessional APCs. Using a combined approach of immunocytochemistry, immunohistochemistry, and flow cytometry analysis we demonstrate that human Schwann cells express the antigen processing and presenting machinery (APM) in vitro and in vivo. Moreover, cultured human Schwann cells increase the expression of proteasome subunit delta (Y), antigen peptide transporter TAP2, and HLA Class I and HLA Class II complexes in an inflammatory environment. In correlation with this observation, Schwann cells in sural nerve biopsies from GBS patients show increased expression of antigen processing and presenting molecules. Furthermore, cultured human Schwann cells can proteolytically digest fluorescently‐labeled nonmammalian antigen ovalbumin. Taken together, our data suggest antigen processing and presentation as a possible function of Schwann cells that may contribute to (auto)immune responses within peripheral nerves. © 2009 Wiley‐Liss, Inc.     

Antibody responses to peptides of peripheral nerve myelin proteins P0 and P2 in patients with inflammatory demyelinating neuropathy

Background

Antibodies with reactivity to peripheral nerve myelin have previously been found in the serum, and bound to peripheral nerves of patients with Guillain–Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).

Aim

To investigate the presence of antibodies reactive to specific peptide sequences within the myelin proteins P0 and P2 in patients with GBS, in patients with CIDP, in healthy controls and in patients with other neuropathies (ON).

Methods

Blood was obtained from 48 patients with GBS, 36 with CIDP, 48 with ON and 38 controls. ELISA was used to detect antibody responses to peptides of the human peripheral myelin proteins P0 and P2. Blood samples were collected from patients with GBS in early, peak and recovery stages of GBS to analyse antibody levels throughout the course of the disease.

Results

Significantly increased total IgG levels were found in patients with GBS compared with other groups. A higher percentage of patients with GBS at the peak of disease had antibody reactivity to P2_14–25 compared with patients with CIDP and control groups. In patients with GBS and CIDP, the percentages of patients with antibody reactivity to P2_61–70, and peptides derived from P0, were comparable to the control groups. Although some individual patients with GBS had high titres of reactivity to the peptide antigens tested, most patients with GBS and CIDP had levels of antibody similar to controls.

Conclusion

Our data suggest that increased IgG levels and increased antibody reactivity to P2 _14–25 in patients with GBS at the peak of disease may play a contributory role in the disease process in some patients with demyelinating forms of GBS.The most common form of Guillain–Barré syndrome (GBS) in Australia is acquired inflammatory demyelinating polyradiculoneuropathy, characterised by primary demyelination and lymphocytic infiltration of the peripheral nerve by macrophages and T cells.¹ Acute motor axonal neuropathy² and acute motor and sensory axonal neuropathy³ are variants of GBS, where axonal damage is the main finding. Clinically and pathologically similar to GBS, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) follows a protracted or relapsing course.⁴ Both GBS and CIDP are considered to be autoimmune diseases involving humoral and cell‐mediated immune reactions.¹ Activation of T and B cells in the peripheral lymphoid organs is thought to be triggered by molecular mimicry between infectious agent antigens and peripheral nerve components.¹ Previous studies have found antibodies to the peripheral myelin proteins P2, P0 and PMP22, α and β tubulin, connexin‐32, gangliosides and glycolipids in the sera of some, but not all, patients with GBS and CIDP.¹We have tested for antibody reactivity to two peripheral nerve myelin proteins using purified peptide antigens from the extracellular domains P0_56–71 and P0_70–85, the cytoplasmic/transmembrane segment P0_180–199 of the glycoprotein P0 as well as P2_14–25 and P2_61–70 of the cytoplasmic basic protein P2. These peptides were also used in our study of T cell reactivity in GBS and CIDP.⁵ Both P2 and P0 have been reported to induce experimental autoimmune neuritis; an animal model of GBS^6,7 and the peptides chosen have previously been found to induce experimental autoimmune neuritis.     

Sural sparing pattern discriminates Guillain–Barré syndrome from its mimics

Introduction: Electrodiagnostic features of demyelination are essential for establishing the diagnosis in demyelinating subtypes of Guillain‐Barré syndrome (GBS), but they may also occur in disorders that mimic GBS clinically. Information about their frequency in GBS mimics is sparse. Methods: Evaluation of electrodiagnostic features from 38 patients with suspected GBS in whom the diagnosis was later refuted (GBS mimics). Their diagnostic accuracy was analyzed by comparison with nerve conduction studies (NCS) from 73 confirmed GBS patients. Results: Disorders that mimicked GBS clinically at the time of hospital admission included other inflammatory, metabolic, toxic, or infectious neuropathies and spinal cord disorders. The sural sparing pattern was the most specific electrodiagnostic feature for demyelinating GBS. Conclusions: Common electrodiagnostic abnormalities in early demyelinating GBS do not usually exclude other rare differential diagnoses. An exception to this is the sural sparing pattern described here, which strongly supports the diagnosis of demyelinating GBS. Muscle Nerve 50 : 780–784, 2014     

Serum antibodies to GM1, GD1b,peripheral nerve myelin,and Campylobacter jejuni in patients with Guillain-Barré syndrome and controls: Correlation and prognosis

Serum antibodies to monosialoganglioside (GM1), disialoganglioside (GD1b), and Campylobacter jejuni, measured by enzyme-linked immunosorbent assay and serum antibodies to peripheral nerve myelin, measured by the C1 fixation and transfer assay, were studied in 58 acute-phase patients with Guillain-Barré syndrome (GBS), 42 disease controls, and 29 normal controls. Anti-peripheral nerve myelin antibodies were elevated in 57 of 58 patients with GBS compared with controls, whereas only 8.6% had increased antibody titers to GM1 and 10.3% to GD1b. Only low antibody titers (GM1) or no antibodies (GD1b) were found in controls. More GBS patients (17.2%) than controls (7%) had antibodies to C jejuni. Poor recovery with inability to walk at 1 year after onset of symptoms was seen in 3 (5%) of the patients with GBS. All 3 patients had serological evidence of recent C jejuni infection but no antibodies to GM1 or GD1b. GBS patients with antibodies to GM1 or GD1b had excellent recovery. Our data indicate that antibodies to GM1 or GD1b do not necessarily mediate the extensive axonal damage seen in these severely affected patients.