Francesca Notturno

Pitfalls in electrodiagnosis of Guillain–Barré syndrome subtypes

Objective To electrophysiologically classify an Italian Guillain–Barré syndrome (GBS) population into demyelinating and axonal subtypes, to investigate how serial recordings changed the classification and to underline the pitfalls in electrodiagnosis of GBS subtypes. Methods The authors applied two current electrodiagnostic criteria sets for demyelinating and axonal GBS subtypes in 55 patients who had at least two serial recordings in three motor and sensory nerves. Results At first test, the electrodiagnosis was almost identical with both criteria: 65–67% of patients were classifiable as acute inflammatory demyelinating polyradiculoneuropathy (AIDP), 18% were classifiable as axonal GBS, and 14–16% were equivocal. At follow-up, 24% of patients changed classification: AIDP decreased to 58%, axonal GBS increased to 38%, and equivocal patients decreased to 4%. The majority of shifts were from AIDP and equivocal groups to axonal GBS, and the main reason was the recognition by serial recordings of the reversible conduction failure and of the length-dependent compound muscle action potential amplitude reduction patterns as expression of axonal pathology. Conclusions Axonal GBS is pathophysiologically characterised not only by axonal degeneration but also by reversible conduction failure at the axolemma of the Ranvier node. The lack of distinction among demyelinating conduction block, reversible conduction failure and length-dependent compound muscle action potential amplitude reduction may fallaciously classify patients with axonal GBS as having AIDP. Serial electrophysiological studies are mandatory for proper diagnosis of GBS subtypes and the identification of pathophysiological mechanisms of muscle weakness. More reliable electrodiagnostic criteria taking into consideration the reversible conduction failure pattern should be devised.

Susceptibility to Guillain-Barré syndrome is associated to polymorphisms of CD1 genes.

Guillain-Barré syndrome (GBS) is the prototype of a postinfectious autoimmune neuropathy. Molecular mimicry between glycolipid antigens expressed by an infective antigen such as Campylobacter jejuni and the human peripheral nerve has been hypothesized to be the causative mechanism of GBS. However, only 1/1000 of C. jejuni enteritis develops GBS. This emphasizes the importance of host-related factors in the development of the disease. HLA studies in GBS failed to show an association or gave conflicting results but MHC class I and II process and present peptides to T lymphocytes making unlikely that the HLA system plays a role in GBS with autoantibodies against self-gangliosides. CD1 molecules are MCH-like glycoproteins specialized in capturing and presenting a variety of glycolipid to antigen-specific T cells. There are five closely linked CD1 genes in humans located in chromosome 1 (named CD1A, B, C, D, and E) all showing limited polymorphism in exon 2 which codifies for the alpha1 domain of CD1 molecules. The nucleotide substitutions in CD1B and CD1C are rare and reported to be silent. In 100 controls and 65 GBS patients (21 with a recent C. jejuni infection and 35 with anti-glycolipid antibodies) we used direct sequencing by polymerase chain reaction to genotype exon 2 of CD1A, CD1D and CD1E genes. CD1D is monomorphic in both controls and patients whereas CD1A and CD1E are biallelic in exon 2. Subjects with CD1E*01/01 genotype are 2.5 times more likely to develop GBS, whereas subjects with CD1A*01/02 or CD1E*01/02 have a reduced relative risk by 3.6 and 2.3 times respectively. The combination of CD1A*01/02 and CD1E*01/02 reduces by 5 times the risk of developing GBS. Although a correlation between CD1E*01/01 genotype and recent C. jejuni infection or presence of antiganglioside antibodies was not found the overall findings indicate that susceptibility to develop GBS is associated with polymorphisms of CD1E and CD1A genes.

Antiganglioside antibodies are associated with axonal Guillain–Barré syndrome: A Japanese–Italian collaborative study

Background Whether or not antiganglioside antibodies are related to axonal or demyelinating Guillain–Barré syndrome (GBS) is still a matter of controversy, as detailed in previous studies conducted in Western and Asian countries. Objective To clarify whether antiganglioside antibodies are associated with axonal dysfunction in Japanese and Italian GBS patient cohorts. Methods Clinical and electrophysiological profiles were reviewed for 156 GBS patients collected from Japan (n=103) and Italy (n=53). Serum IgG antibodies against GM1, GM1b, GD1a and GalNAc-GD1a were measured by ELISA in the same laboratory. Electrodiagnostic criteria and results of serial electrophysiological studies were used for classification of GBS subtypes: acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). Results In both Japanese and Italian cohorts, any of the antibodies were positive in 36% of the patients, and antibody positivity had a significant association with the AMAN electrodiagnosis. Approximately 30% of Japanese and Italian antiganglioside positive patients showed the AIDP pattern at the first examination whereas sequential studies showed that most finally showed the AMAN pattern. Clinically, seropositive patients more frequently had preceding diarrhoea and pure motor neuropathy in both Japanese and Italian cohorts; vibratory sensation was normal in 97% of Japanese and in 94% of Italian seropositive patients. Conclusions In GBS, clinical and electrophysiological features appear to be determined by antiganglioside antibodies, and the antibodies are associated with motor axonal GBS in both Japan and Italy. Classification of the GBS subtypes as a disease entity should be made, combining the results of antiganglioside assays and serial electrodiagnostic studies.

Local and remote effects of transcranial direct current stimulation on the electrical activity of the motor cortical network

We systematically investigated the effects of cathodal and anodal Transcranial Direct Current Stimulation (CtDCS, AtDCS) on the electric activity of primary motor cortex during a motor task. High‐density electroencephalography was used to define the spatial diffusion of tDCS after effects. Ten healthy subjects performed a finger tapping task with the right hand before and after three separate sessions of 20 minutes of Sham, AtDCS or CtDCS over left primary motor cortex (M1). During movement, we found an increment of low alpha band Event‐Related Desynchronization (ERD) in bilateral central, frontal areas and in the left inferior parietal region, as well as an increment of beta ERD in fronto‐central and parieto‐occipital regions, after AtDCs compared to Sham and CtDCS. In the rest pre‐movement period, after Sham as well as AtDCS, we documented an increment of low alpha band power over the course of pre‐ and post‐stimulation recording sessions, localized in the sensorimotor and parieto‐occipital regions. On the contrary, after CtDCS no increment of low alpha power was found. Finally beta band coherence among signals from left sensorimotor cortex and activity of bilateral parietal, occipital and right frontal regions was higher after AtDCS compared with Sham condition. Similarly, theta coherence with parietal and frontal regions was enhanced after AtDCS. We hypothesize that the local modulation of membrane polarization, as well as long‐lasting synaptic modification induced by tDCS over M1, could result in changes of both local band power and functional architecture of the motor network. Hum Brain Mapp 35:2220–2232, 2014.

Involvement of sensory fibres in axonal subtypes of Guillain–Barré syndrome

Background Acute motor axonal neuropathy (AMAN) and acute motor and sensory axonal neuropathy (AMSAN) are due to an antiganglioside antibody mediated attack, thought to be restricted to motor fibres in AMAN. Sensory symptoms and minor sensory conduction abnormalities, however, have been reported in some AMAN patients. Objective To verify whether sensory fibres are truly spared in AMAN and whether AMAN and AMSAN represent a continuum. Methods Serial conduction studies in 13 AMAN and three AMSAN patients were reviewed. To evaluate the variation in sensory nerve action potential (SNAP) amplitude in serial recordings, the least significant change in a test–retest study of 20 controls was calculated. Least significant change for median, ulnar and sural nerves were 44%, 47% and 58%, respectively. Results In 34% of initially normal sensory nerves of six AMAN patients, SNAP amplitude significantly increased by 57–518%. In three nerves of three AMAN patients, SNAP significantly decreased by 50–69%. Overall, serial recordings allowed detection of sensory fibre involvement in 49% of nerves and in 69% of AMAN patients. In one AMSAN patient, SNAP increased in two nerves by 150–300%; in another patient, SNAPs, unrecordable at baseline in six nerves, reappeared during follow-up and normalised in three nerves. In five nerves of three AMAN and in eight nerves of two AMSAN patients, SNAP amplitudes increased rapidly, suggesting reversible conduction failure of sensory fibres. In other nerves, SNAP increased over months, as for axonal regeneration. Conclusions Sensory fibres are often involved subclinically in AMAN. Reversible conduction failure may develop in sensory as well as motor fibres in both AMAN and AMSAN. AMAN and AMSAN represent a continuum in axonal GBS.

Acute sensory ataxic neuropathy with antibodies to GD1b and GQ1b gangliosides and prompt recovery

Three patients developed acute pure sensory ataxic neuropathy. Two of the three patients had a recent Campylobacter jejuni infection. Patient 1 had monospecific IgG anti‐GD1b. Patients 2 and 3 had cross‐reactive IgG anti‐GQ1b and anti‐GD1b and patient 2 also had IgG anti‐GT1a. Motor nerve conduction studies were completely normal. Sensory conductions showed reduced amplitude or absent sensory nerve action potentials with normal or slightly slowed conduction velocities. In patient 2, serial electrophysiological studies showed reappearance and improvement of sensory nerve potential amplitudes in 4 weeks. All patients recovered completely in 2 months and sensory potential amplitudes normalized in 3–5 months. Our findings: (1) confirm the existence of a pure acute sensory ataxic neuropathy with cross‐reactive IgG anti‐GQ1b and anti‐GD1b as a variant of Guillain–Barré syndrome; (2) expand the clinical presentation of Guillain–Barré syndrome after C. jejuni infection and suggest that molecular mimicry is at the basis of acute sensory ataxic neuropathy; and (3) indicate that, in acute sensory ataxic neuropathy with prompt recovery, the site of the lesion is not in the primary sensory neurons and the pathophysiological mechanism may be functional in nature. Muscle Nerve, 2007

Reversible conduction failure in pharyngeal-cervical-brachial variant of guillain-barré syndrome

In two patients with the pharyngeal–cervical–brachial variant (PCB) of Guillain–Barré syndrome (GBS), low amplitude distal compound muscle action potentials and partial motor conduction blocks normalized without development of excessive temporal dispersion within 4 weeks. Sensory nerve action potentials significantly improved in amplitude or, when absent, rapidly became recordable at follow‐up. Besides axonal degeneration, PCB is characterized by reversible conduction failure in both motor and sensory fibers and is in the continuous spectrum of axonal GBS subtypes. Muscle Nerve, 2010

Polymorphisms of CD1 genes in chronic dysimmune neuropathies

CD1 are MCH-like glycoproteins specialized in capturing and presenting glycolipid to T cells. Expression of CD1 molecules has been observed on endoneurial machrophages in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and vasculitis and polymorphisms of CID1A and CD1E genes have been associated with susceptibility to develop Guillain-Barré syndrome. In 46 patients with CIDP, in 13 patients with multifocal motor neuropathy and in 132 controls we genotyped exon 2 of CD1A and CD1E genes. We found no association between chronic dysimmune neuropathies, with or without anti-ganglioside antibodies, and polymorphisms of CD1A and CD1E genes.

Autoantibodies to neurofascin-186 and gliomedin in multifocal motor neuropathy

We tested autoantibodies to neurofascin-186 (NF186) and gliomedin in sera from patients with multifocal motor neuropathy (MMN, n=53) and chronic inflammatory demyelinating polyneuropathy (CIDP, n=95) by ELISA. IgG antibodies to NF186 or gliomedin were found in 62% of MMN and 1% of CIDP sera, and IgM antibodies to the same antigens in 12% of MMN and 1% of CIDP sera. These autoantibodies activated complement. Ten percent of the MMN sera without IgM anti-GM1 reactivity had anti-NF186 antibodies. Because NF186 and gliomedin play a crucial role for salutatory conduction, the autoantibodies may contribute to produce motor nerve conduction block and muscle weakness in MMN.

Susceptibility to chronic inflammatory demyelinating polyradiculoneuropathy is associated to polymorphic GA repeat in the SH2D2A gene

The SH2D2A gene encodes a T-cell-specific adapter protein involved in the negative control of T-cell activation. The genotype GA13-16 homozygote of the SH2D2A gene promoter has been associated with the susceptibility to develop multiple sclerosis. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated neuropathy sharing several pathogenetic mechanisms with multiple sclerosis. We genotyped the SH2D2A promoter region in 105 controls and 48 patients with CIDP. We found a significant association between CIDP and the genotype GA13-16 homozygote (OR 3.167; p 0.013). We hypothesize that this genotype is associated with the susceptibility to develop CIDP and may be implicated in the persistence of the disease.