Chronic inflammatory lumbosacral polyradiculopathy: a regional variant of CIDP.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) affects various components and segments of the peripheral nervous system differently, and thus there can be phenotypic heterogeneity. We report a 47-year-old woman with chronic sensory disturbances and proximal weakness limited to the legs. Motor and sensory nerve conduction studies were normal. Somatosensory evoked potentials and imaging indicated a demyelinating process involving the lumbosacral roots. The patient responded favorably to IVIg. Although she did not fulfill the diagnostic criteria for CIDP we believe this patient represents a restricted regional CIDP variant.

Polymorphism of CD1 and SH2D2A genes in inflammatory neuropathies.

In the quest for susceptibility factors of inflammatory neuropathies, many genes implicated in the pathogenesis of autoimmune diseases have been investigated with negative or conflicting results. We studied, with a gene candidate approach, the CD1 system specialized in capturing and presenting glycolipids to antigen-specific T cells, and the SH2D2A gene encoding for a T-cell-specific adapter protein implicated in control of early T-cell activation. In Guillain-Barré syndrome, an initially positive association study with polymorphism of CD1A and CD1E genes was not confirmed. In chronic inflammatory demyelinating polyneuropathy, we did not find an association with CD1 genes, but we found an association with a homozygous genotype for a low repeat number of tandem GA in the SH2D2A gene. This genotype could result in defective control and elimination of autoreactive T cells. All the studies were performed on relatively small size populations. Confirmation in larger sized studies is required both for CD1 and SH2D2A genes. Considering the relative rarity of patients with inflammatory neuropathies, this can only be accomplished by international collaboration.

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.

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.

Experimental axonopathy induced by immunization with Campylobacter jejuni lipopolysaccharide from a patient with Guillain-Barré syndrome.

New Zealand white rabbits were immunized with a lipopolysaccharide (LPS) extracted from a Campylobacter jejuni HS:19 strain isolated from a GBS patient expressing GM1 and GD1a-like epitopes, Freund's adjuvant (group I) and Freund's adjuvant plus keyhole lympet hemocyanin (KLH) (group II). Both groups showed high titers of anti-LPS and anti-GM1 and lower titers of anti-GD1b and anti-GD1a antibodies. Weakness and axonal degeneration in sciatic nerves was detected in 1/11 of group I and 6/7 of group II. This model replicates, at least in part, the pathogenetic process hypothesized in the human axonal GBS with antiganglioside antibodies post C. jejuni infection and indicates that KLH plays an additional role in neuropathy induction.

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.

Capsular warning syndrome mimicking a jacksonian sensory march.

A 57-year-old man, operated eight years before for a left frontal falx meningioma, presented with short lasting, stereotyped episodes of paresthesias ascending from the right foot to the hand. A diagnosis of somatosensory seizures with jacksonian march was made. The patient was given antiepilectics but 5 days later, a few hours after another paresthesic episodes, he developed right hemiplegia, hemianesthesia and dysartria due to an infarct of left capsular posterior limb. We deem that in this patient the paresthesic episodes were more likely an expression of a capsular warning syndrome than of parietal epilepsy because of the frontal localization of the surgical lesion, the absence of motor components in all episodes, the negativity of repeated EEG, and the lack of recurrences after stroke. In capsular warning syndrome sensory symptoms mimicking a jacksonian march can be due to ischemic depolarization progressively recruiting the somatotopically arranged sensory fibers in the posterior capsular limb.

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.

Glial fibrillary acidic protein: a marker of axonal Guillain-Barrè syndrome and outcome.

Glial fibrillary acid protein (GFAP) is increased in serum and cerebrospinal fluid of patients with dementia, traumatic brain injury, stroke, and multiple sclerosis. To determine whether GFAP is increased in Guillain-Barré syndrome (GBS) we evaluated serum GFAP in 30 controls, 20 patients with acute inflammatory demyelinating neuropathy (AIDP), and 17 with primary axonal GBS. Serum GFAP levels were increased in axonal GBS (median, 0.74) compared with controls (median, 0.41; P < 0.0001) and AIDP (median, 0.58; P = 0.0015). GFAP levels correlated with Hughes grades (serum r = 0.74; P < 0.0001) 6 months after neuropathy onset. Applying the cutoff value in serum of 0.63 to the diagnosis of axonal GBS, we obtained a sensitivity of 76.5% and a specificity of 86%. Thus, serum GFAP levels may be used in GBS as a diagnostic marker of the axonal variant and to predict outcome.

Persistent multifocal conduction block in vasculitic neuropathy with IgM anti-gangliosides.

A 30-year-old man with essential cryoglobulinemia presented with an axonal neuropathy and was found to have vasculitis at nerve biopsy. After 44 months, in accord with clinical deterioration, motor conduction studies showed excessive temporal dispersion multifocally, with partial conduction block persisting for 3 years. Antibody testing showed the presence of IgM anti-GM1, anti-GD1a, and anti-GM2 antibodies. Transitory conduction block has been reported occasionally in patients with vasculitis. The persistent multifocal conduction abnormalities found in this patient were more likely due to a superimposed immunomediated demyelination rather than to chronic nerve ischemia secondary to vasculitis.

Predictors of response to rituximab in patients with neuropathy and anti-myelin associated glycoprotein immunoglobulin M.

We evaluated the efficacy and safety of rituximab in an open-label, uncontrolled study of 13 patients with polyneuropathy associated with antibodies to myelin-associated glycoprotein (MAG) and correlated the response to therapy with clinical and laboratory features. One year after rituximab therapy, anti-MAG immunoglobulin M (IgM) titers were significantly reduced. At that time, eight patients (62%) had improved in both the inflammatory neuropathy cause and treatment (INCAT) sensory sumscore and the Medical Research Council sumscore for muscle strength and seven of them also in the INCAT disability score. The improvement in the mean INCAT sensory sumscore was significant at 12 months and correlated with lower anti-MAG antibody at entry and at follow-up. This study suggests that rituximab may be efficacious in patients with anti-MAG associated neuropathy and particularly on sensory impairment and in those with moderately elevated antibody titers. These findings suggest that antibody reduction below a critical level may be necessary to achieve clinical improvement.

Lewis-Sumner syndrome in hepatitis C virus infection: a possible pathogenetic association with therapeutic problems.

A patient with chronic hepatitis from hepatitis C virus (HCV) infection developed Lewis-Sumner syndrome (LSS). The neuropathy worsened after intravenous immunoglobulins, remitted after intravenous methylprednisolone, relapsed during interferon-alpha, but responded again to steroids continued for 68 weeks with clinical remission and without worsening of hepatitis. We are not aware of other reports of HCV infection and LSS. This association may be coincidental or related to a virus-triggered immune-mediated process. Although the coexistence of a dysimmune neuropathy with hepatitis makes problematic the choice of treatment, we emphasize that the patient's condition during treatment with steroids and the 46 following weeks without therapy has been excellent.