Kei Funakoshi

Anti-GM1 Antibodies Cause Complement-Mediated Disruption of Sodium Channel Clusters in Peripheral Motor Nerve Fibers

Voltage-gated Na+ (Nav) channels are highly concentrated at nodes of Ranvier in myelinated axons and facilitate rapid action potential conduction. Autoantibodies to gangliosides such as GM1 have been proposed to disrupt nodal Nav channels and lead to Guillain-Barré syndrome, an autoimmune neuropathy characterized by acute limb weakness. To test this hypothesis, we examined the molecular organization of nodes in a disease model caused by immunization with gangliosides. At the acute phase with progressing limb weakness, Nav channel clusters were disrupted or disappeared at abnormally lengthened nodes concomitant with deposition of IgG and complement products. Paranodal axoglial junctions, the nodal cytoskeleton, and Schwann cell microvilli, all of which stabilize Nav channel clusters, were also disrupted. The nodal molecules disappeared in lesions with complement deposition but no localization of macrophages. During recovery, complement deposition at nodes decreased, and Nav channels redistributed on both sides of affected nodes. These results suggest that Nav channel alterations occur as a consequence of complement-mediated disruption of interactions between axons and Schwann cells. Our findings support the idea that acute motor axonal neuropathy is a disease that specifically disrupts the nodes of Ranvier.

Dysfunction of nodes of Ranvier: a mechanism for anti-ganglioside antibody-mediated neuropathies.

Autoantibodies against gangliosides GM1 or GD1a are associated with acute motor axonal neuropathy (AMAN) and acute motor-sensory axonal neuropathy (AMSAN), whereas antibodies to GD1b ganglioside are detected in acute sensory ataxic neuropathy (ASAN). These neuropathies have been proposed to be closely related and comprise a continuous spectrum, although the underlying mechanisms, especially for sensory nerve involvement, are still unclear. Antibodies to GM1 and GD1a have been proposed to disrupt the nodes of Ranvier in motor nerves via complement pathway. We hypothesized that the disruption of nodes of Ranvier is a common mechanism whereby various anti-ganglioside antibodies found in these neuropathies lead to nervous system dysfunction. Here, we show that the IgG monoclonal anti-GD1a/GT1b antibody injected into rat sciatic nerves caused deposition of IgG and complement products on the nodal axolemma and disrupted clusters of nodal and paranodal molecules predominantly in motor nerves, and induced early reversible motor nerve conduction block. Injection of IgG monoclonal anti-GD1b antibody induced nodal disruption predominantly in sensory nerves. In an ASAN rabbit model associated with IgG anti-GD1b antibodies, complement-mediated nodal disruption was observed predominantly in sensory nerves. In an AMAN rabbit model associated with IgG anti-GM1 antibodies, complement attack of nodes was found primarily in motor nerves, but occasionally in sensory nerves as well. Periaxonal macrophages and axonal degeneration were observed in dorsal roots from ASAN rabbits and AMAN rabbits. Thus, nodal disruption may be a common mechanism in immune-mediated neuropathies associated with autoantibodies to gangliosides GM1, GD1a, or GD1b, providing an explanation for the continuous spectrum of AMAN, AMSAN, and ASAN.

Complement inhibitor prevents disruption of sodium channel clusters in a rabbit model of Guillain–Barré syndrome

Complement-mediated disruption of voltage-gated sodium channels at the nodes of Ranvier acts in the development of acute motor axonal neuropathy. Nafamostat mesilate, a synthetic serine protease inhibitor, used in clinical practice for more than 20 years, has anti-complement activity. Acute motor axonal neuropathy rabbits obtained by GM1 ganglioside sensitization were or were not given nafamostat mesilate intravenously. Complement deposition and sodium channel disruption in the spinal anterior roots were significantly less frequent in the treated rabbits than in the controls. Nafamostat mesilate inhibited complement deposition and prevented sodium channel disruption. This provided the rationale for a clinical trial.

Clinical predictors of mechanical ventilation in Fisher/Guillain-Barre overlap syndrome

Background: Some patients with Fisher syndrome (FS) developed subsequent descending tetraparesis (Fisher/Guillain–Barré overlapping syndrome: FS/GBS). The assumption is that such descending progression may frequently lead to respiratory failure. Objective: To investigate whether patients with FS/GBS more often require artificial ventilation than those with typical GBS and which clinical and serological findings are useful predictors. Methods: Medical records were reviewed of patients who had acute ophthalmoplegia, ataxia and areflexia, as well as subsequent tetraparesis with monophasic course. Forty-five patients fulfilled the FS/GBS criteria. Clinical and serological features were analysed, and clinical predictors of mechanical ventilation were investigated. Results: FS/GBS patients more frequently required mechanical ventilation than did GBS patients (24% vs 10%, p = 0.04). The former also needed artificial ventilation earlier than the latter (p = 0.03), but none of the FS patients required it. As the initial symptom, ventilated FS/GBS patients more frequently showed titubation than non-ventilated patients (55% vs 18%, p = 0.04). During the course of the illness, descending tetraparesis was more common in 11 ventilated FS/GBS patients than in the other 34 non-ventilated patients (64% vs 21%, p = 0.02). The need for artificial ventilation was not associated with anti-GQ1b IgG antibodies, monospecific anti-GT1a IgG antibodies or IgG antibodies to various ganglioside complexes. Conclusions: FS/GBS patients significantly needed mechanical ventilation more often. Such patients showing titubation and descending tetraparesis need to be carefully monitored as the illness progresses because those clinical features are helpful predictors of respiratory failure.

Prospective study on anti-ganglioside antibodies in childhood Guillain-Barré syndrome

Background: Antiganglioside antibodies have been reported to play a part in the pathophysiology of Guillain–Barré syndrome (GBS). Aims: To investigate the prevalence and correlation of anti-ganglioside antibodies with clinical data in children with GBS in a multicentre clinical trial. Methods: Immunoglobin (Ig)G and IgM to GM1, GM1b, GD1a, GalNAc–GD1a, GD1b, GT1a, and GQ1b were measured by ELISA in sera obtained before treatment. In addition, serological testing for Campylobacter jejuni was carried out. In parallel, a group of adults with GBS and a control group of children without GBS or other inflammatory diseases were evaluated. Results: Sera from 63 children with GBS, 36 adults with GBS and 41 children without GBS were evaluated. Four of the children with GBS showed positive IgG to GM1, in one case combined with anti-GalNAc–GD1a and in one with anti-GD1b. Two others showed isolated positive IgG to GD1b and GT1a. One showed increased anti-GalNAc–GD1a IgM. In 5 of the 63 children, serological evidence of a recent infection with C jejuni was found, and this correlated significantly with the raised antibodies (p = 0.001). In the control group without GBS, no child showed positive IgG, but one showed anti-GalNAc–GD1a IgM. Compared with the adults with GBS, the frequency of antibodies in children was insignificantly lower. In our study, patients with positive antibodies did not show a more severe GBS course or worse outcome than those who were seronegative, and we could not show an increased incidence of axonal dysfunction. Conclusions: In some children with GBS, one can detect raised IgG against various gangliosides, similar to that in adults. A recent infection with C jejuni is markedly associated with the presence of these antibodies. However, in contrast with what has been reported in adults, in this study we were unable to show a negative effect of these findings on the clinical course.

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. Muscle Nerve, 2005

Parvovirus B19 infection antedating Guillain–Barre’ syndrome variant with prominent facial diplegia

The clinical spectrum of Guillain–Barre syndrome (GBS) has expanded due to variants accounting for benign forms without progression [1–4]. Patients with acute onset of facial diplegia, with or without limb weakness, acral paraesthesias, or areflexia are affected by a regional GBS variant ‘‘facial diplegia and paraesthesias’’ (FDP) [1, 3]. This 36 year old man, 3 weeks after high fever with myalgias, experienced facial pain, difficulty in closing eyes, and pursuing lips. Taste, lacrimation, swallowing, and hearing were normal. On admission (day 2), neurological examination showed facial diplegia and areflexia. Eye movements, strength, coordination, and sensibility were unaffected. By day 4, the patient reported hand numbness. Normal laboratory tests included screening for autoimmune-rheumatic diseases. Virological, microbiological studies excluded a variety of infections (Borrelia burgdorferi, HSV-1/2, VZV, EBV, CMV, HHV-6). Serum IgG and IgM antibodies to gangliosides GM1, GM2, GM1b, GD1a, GD1b, GalNAc-GD1a, GT1a, and GQ1b were investigated (day 3) by enzyme-linked immunosorbent assay (ELISA) as described elsewhere [2, 3]. The antiganglioside antibody assays were negative. CSF (day 5) showed increased protein content (68 mg/dl, normal \ 45). ELISA revealed anti HPV-B19 IgM and IgG (titer above 5.99). Real Time PCR detected a viral load of 28,794 copies/ml. N-PCR showed HPV-B19 DNA in CSF. Electrophysiological study (day 8) showed temporally dispersed peroneal, tibial compound muscle action potentials (1.5–2 mV in amplitude, normal [ 4), border-line slowing in motor conduction (40 m/sec normal [ 45), and delayed peroneal, tibial F-waves (65 ms, normal \ 58). There were proximal conduction blocks in median and ulnar nerves [5]. Sensory fibers were spared. Brain MRI, auditory, and brain stem evoked responses were normal. Intravenous immunoglobulin was started on day 5 (IVIg 0.4 g/kg/daily) and completed over the next five days. By 3 weeks, bifacial weakness and distal numbness had recovered; on day 122, there were neither residual clinical nor electrophysiological abnormalities. ELISA (day 127) showed anti B19 IgM titer lowered to 0.79, whereas IgG remained 5.99 (Biotrin international ltd, Dublin, Ireland).Our patient presented with a post-infectious FDP variant [3]. Major features were albumino-cytologic dissociation and presence of HPV-B19 DNA in serum and CSF during the acute phase. Susuki et al. [3] reported 22 cases with a disease compatible with Ropper’s original description [1]; among those patients, marginal cases were identified without limb paraesthesias or areflexia [3]. Infection serologies during the acute phase evidenced anti-cytomegalovirus, Campylobacter jejuni, Epstein-Barr, Borrelia burgdorferi, and Mycoplasma pneumoniae IgM antibodies in 14 subjects; 13 experienced upper respiratory tract infection. Anti-ganglioside IgM antibodies were detected in five patients. Motor conduction study suggested demyelination in 14 cases and was normal in 7 [3]. HPV-B19 causes erythema infectiosum, aplastic crisis, fetal hydrops, arthritis, vasculitis, and neurological syndromes [6–9]. Skin rashes or arthralgias associated with positive rheumatoid factor and antinuclear antibodies F. Barbi A. Ariatti G. Galassi (&) Department of Neurosciences, University of Modena and Reggio Emilia, Via P. Giardini, 1350, 41010 Modena, Italy e-mail: giulianagalassi@aliceposta.it

Paraparetic Guillain-Barré syndrome: Extending the axonal spectrum

There are few reports of the paraparetic variant of Guillain‐Barré syndrome, and its pathophysiology is not well understood. We report a patient presenting with acute paraparesis following diarrhea. Serial nerve conduction studies suggested primary axonal injury, and not demyelination, predominantly in the lower limbs compared with the upper limbs. There was serological evidence of recent Campylobacter jejuni infection and strongly positive immunoglobulin G anti‐GD1a antibodies. Paraparetic Guillain‐Barré syndrome is likely to represent a regional form of Guillain‐Barré syndrome, with a nosological position within the axonal subtype.

Delirium in two patients with Bickerstaff's brainstem encephalitis

In this report, we describe the case of two patients with Bickerstaffs brainstem encephalitis (BBE) who developed delirium manifested as emotional incontinence, restlessness, and aggressive behavior from disease onset. Serum anti-GQ1b and anti-GT1a IgG antibodies were detected in both patients. When unusual psychiatric symptoms are observed, in addition to acute ophthalmoplegia and ataxia, neurologists should take into account the possibility of BBE. Brain MRI findings were normal in both patients and SPECT was performed on only patient 1. SPECT of patient 1 showed reversible hypoperfusion in the brainstem, bilateral thalami, and medial frontal lobe. Brain SPECT appears to be useful for detecting lesions of the brainstem as well as the basal ganglia or cerebrum in BBE.

Severe cranial nerve involvement in a patient with monoclonal anti-MAG/SGPG IgM antibody and localized hard palate amyloidosis

We report a patient with severe cranial polyneuropathy as well as sensory limb neuropathy. Biclonal serum IgM-kappa/IgM-lambda gammopathy was found and serum anti-myelin-associated glycoprotein (MAG)/sulfoglucuronyl paragloboside (SGPG) IgM antibody was also detected. Immunofluorescence analysis of a sural nerve biopsy specimen revealed binding of IgM and lambda-light chain on myelin sheaths. No amyloid deposition was detected in biopsied tissues except for the hard palate, suggesting that the amyloidosis was of the localized type and had no relation to the pathogenesis of cranial neuropathy. Our observations indicate that the anti-MAG/SGPG IgM antibody may be responsible for this patients cranial polyneuropathy, which is a rare manifestation in anti-MAG/SGPG-associated neuropathy.