Antibodies to peripheral nerve myelin proteins in chronic inflammatory demyelinating polyradiculoneuropathy

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired disorder of the peripheral nervous system with a probable auto-immune pathogenesis. The nature of the responsible autoantigens is unclear in most patients. We used the Western immunoblot technique to seek antibodies to peripheral nerve protein antigens. Sera from eight of 32 (25%) CIDP patients, 12 of 37 (32%) Guillain-Barré syndrome (GBS) patients, zero of 30 (0%) chronic idiopathic axonal polyneuropathy patients and two of 39 (5%) healthy control subjects contained anti-peripheral nerve protein antibodies. The frequency of such antibodies was significantly greater in both CIDP (p = 0.04) and GBS (p = 0.003) patients than in normal control subjects. For CIDP patients, there were non-significant trends for antibodies to be more common in females and in those who responded to treatment with either intravenous immunoglobulin or plasma exchange. The commonest antibodies were directed against a band at 28 kDa, resembling that labelled by a monoclonal antibody against myelin protein zero (P0). Six CIDP and seven GBS patients' sera reacted with this band. These results support the view that antibodies to myelin proteins, and especially P0, are present in the serum of some patients with CIDP and GBS.     

Class and IgG subclass distribution of antibodies against peripheral nerve myelin in sera from patients with inflammatory demyelinating polyradiculoneuropathy

An enzyme-linked immunosorbent assay (ELISA) was used to quantify antibodies against peripheral nerve myelin (PNM) in sera from 90 patients with Guillain-Barré syndrome (GBS) and from 70 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Fifty-nine percent of the patients with GBS and 51% of the patients with CIDP had increased levels of anti-PNM antibodies. Antibodies were also found in 0%-14% of sera from patients with other neurological diseases and in 8% of normal blood donors. Mean levels of IgG, IgM and IgA anti-PNM antibodies were increased in sera from patients with GBS, and mean IgG and IgA anti-PNM antibody levels were increased in sera from patients with CIDP when compared with sera from normal blood donors. The mean IgG anti-PNM antibody response observed in patients with GBS or CIDP was dominated by the IgG1 and IgG3 subclasses.     

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.     

Antibodies to peripheral nerve tissue in sera from patients with acute Guillain-Barré syndrome demonstrated by a mixed haemagglutination technique

The mixed haemagglutination technique (MA) was used to demonstrate antibodies to peripheral nerve tissue (PNS) in sera from patients with acute Guillain-Barré syndrome (GBS). Within the first 2 weeks of the disease IgG antibodies were detected in sera from 15 of 42 patients (36%). Antibodies were detected in 60% of the patients with severe GBS, and in 30% of those with a mild GBS. The highest titres were found in the sera from the most severely affected patients and could be detected after 48 days of the illness in one of the sera. Sera from healthy blood donors and from patients with various other diseases did not contain PNS. The MA technique is reproducible and is more sensitive than the indirect immunofluorescence test and the antiglobulin consumption test.     

Are CSF or serum ganglioside antibodies related to peripheral nerve demyelination in neuroborreliosis,Guillain-Barré syndrome,or chronic inflammatory demyelinating polyradiculoneuropathy?

Summary Cerebrospinal fluid (CSF) and serum IgG and IgM antibodies to seven gangliosides were determined in patients with neuroborreliosis (NB) (n=20), Guillain-Barré syndrome (GBS) (n=13), and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) (n=10). the incidence of elevated antibodies was highest in NB and lowest in CIDP. Correlation between CSF and serum antibodies was only observed for IgG antibodies to GM1 GD1b and GT1b in GBS. The strong IgM antibody reactivity to gangliosides in the CSF of NB patients may be involved in the variety of neurological disorders attributed toBorrelia burgdorferi infection. Since one CIDP and three GBS patients had serologic evidence of prior or concurrent borrelia infection, this infection may belong to the infections that can trigger GBS or CIDP. The lack of specific ganglioside antibody patterns in these four patients suggests that ganglioside antibodies are not the link betweenBorrelia burgdorferi infection and the demyelination of peripheral nerves in GBS and CIDP.Some results reported in this study have been presented at the Second Congress of the Pan-European Society of Neurology in Vienna, Austria, December 1991.     

Anti‐ganglioside antibodies in Guillain–Barré syndrome and chronic inflammatory demyelinating polyneuropathy in Chinese patients

Introduction: In this study we investigated the relationships between anti‐ganglioside antibodies and Guillain–Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP). Methods: Samples from 48 Chinese patients diagnosed with GBS and 18 patients diagnosed with CIDP were retrospectively reviewed. Results: In the GBS patients, 62.5% were classified as having acute inflammatory demyelinating polyneuropathy (AIDP), 27.1% were found to have acute motor axonal neuropathy (AMAN), and 10.4% were unclassified. Serum IgG anti‐ganglioside antibodies were detected in 46.2% of the AMAN patients and in 6.7% of the AIDP patients (P < 0.05); 5.6% of the 18 CIDP patients were IgG antibody positive, and 27.8% were IgM antibody positive. Facial palsy and sensory impairment were significantly associated with IgM antibodies. Conclusions: These results suggest that IgG anti‐GM1 antibodies are associated with AMAN, but not with AIDP, and that IgM antibodies against GM1, GM2, and GM3 are associated with facial nerve palsy. Muscle Nerve 55 : 470–475, 2017     

Genetics of Guillain‐Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): current knowledge and future directions

Guillain‐Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are thought to be autoimmune diseases. There have been many attempts to find a human leukocyte antigen (HLA) association with GBS and CIDP with little success. There have been studies of other plausible genes in GBS and CIDP and the role of these genes in GBS and CIDP and the data from these genetic studies is reviewed. Some of the genes that have been studied are immune related and some others have nervous system effects. The studies are limited by small numbers. Some of the genes show association with disease severity rather than disease susceptibility. The need for more detailed molecular studies of the role of HLA molecules and the need for modern genetic approaches to GBS and CIDP are explained.     

Early electrophysiological findings in acute inflammatory demyelinating polyradiculoneuropathy variant of Guillain‐Barre syndrome in the Pakistani population – a comparison with global data

Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and acute motor axonal neuropathy are the most common variants of Guillian‐Barre syndrome documented in the Asian population. However, the variability of early neurophysiologic findings in the Asian population compared to western data has not been documented. Eighty‐seven cases of AIDP were retrospectively reviewed for their demographic, clinical, electrophysiological, and laboratory data. Mean age of subjects was 31 ± 8 years with males more commonly affected. Motor symptoms (97%) at presentation predominated. Common early nerve conduction findings included low motor amplitudes (85%), recordable sural sensory responses (85%), and absent H‐reflex responses (65%). Prolonged F‐latencies were found most commonly in posterior tibial nerves (23%) in the lower limbs and median and ulnar nerves (18%) in the upper limbs. Blink reflex (BR) studies were performed in 57 patients and were abnormal in 80% of those with clinical facial weakness and in 17 of 52 patients (33%) with no clinical cranial nerve signs, suggesting subclinical cranial nerve involvement. Abnormal motor and sensory amplitudes are seen early. Prolonged distal latencies, temporal dispersion/conduction blocks and sural sparing pattern are other common early nerve conduction study findings of AIDP seen in the Pakistani population. There are no significant differences in abnormalities of conduction velocities and delayed reflex responses compared to published data. The BR can help in the early diagnosis of AIDP.     

Chronic inflammatory demyelinating polyradiculoneuropathy with diffuse and massive peripheral nerve hypertrophy: Distinctive clinical and magnetic resonance imaging features

We present 3 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with extensive and diffuse hypertrophy of the nerve roots and peripheral nerves. They exhibited slowly progressive sensory impairment and distally predominant limb weakness and muscular atrophy, and markedly enlarged palpable nerve trunks. They responded beneficially to corticosteroid. Magnetic resonance imaging demonstrated diffuse and extensive hypertrophy of the peripheral nerves in the four limbs and the spinal nerve roots, with gadolinium enhancement in the nerve roots but not in the peripheral nerves. These patients were considered to have a hypertrophic variant of CIDP. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:805–808, 1998.     

Serum antibodies to GM1 and GM3-gangliosides in systemic lupus erythematosus with chronic inflammatory demyelinating polyradiculoneuropathy

Acute symmetric demyelinating polyneuropathy of the Guillain-Barré type is known in systemic lupus erythematosus (SLE). Chronic idiopathic demyelinating polyneuropathy (CIDP) has been reported rarely with SLE. A case is reported of CIDP accompaning SLE with autoantibodies against GM1-and GM3-gangliosides. There was no historical evidence to suggest SLE, and CIDP was the first manifestation of SLE. The 38-year-old patient had elevated CSF-protein, slow nerve conduction velocities, sural nerve biopsy revealed mixed axon loss with demyelination and CIDP white matter lesions were observed in magnetic resonance imaging. the GM1-and GM3-autoantibodies may play a role in the pathogenesis of CIDP in SLE.     

Peripheral nerve size in normals and patients with polyneuropathy: An ultrasound study

Ultrasound has been used for visualizing peripheral nerve pathology. Our goal was to use ultrasound to quantitate the sizes of upper extremity nerves along their length in control subjects and patients with neuropathy. We measured median and ulnar nerve cross‐sectional areas (NCSA) in the arms of 190 subjects, including 100 with neuropathies and 90 controls. We found that NCSAs in healthy child and adult controls were greater with increasing height, at proximal sites, and at sites of entrapment. Nerves were enlarged in all Charcot–Marie–Tooth 1A (CMT‐1A) (11 of 11; 100%), most chronic inflammatory demyelinating polyneuropathy (CIDP) (31 of 36; 86%), half of Guillain–Barré syndrome (GBS) (8 of 17; 47%), but few axonal neuropathy (7 of 36, 19%) subjects. In GBS, nerve enlargement occurred early and with minimal electrodiagnostic abnormalities in some patients. We conclude that NCSA measured by ultrasound is a quantifiable marker of nerve features that should be corrected for patient characteristics and nerve site. NCSA is generally larger in demyelinating than it is in axonal polyneuropathies. Muscle Nerve, 2009     

Cerebrospinal fluid and serum from patients with inflammatory polyradiculoneuropathy have opposite effects on sodium channels

The effects of cerebrospinal fluid (CSF) and serum from patients having Guillain–Barré syndrome (GBS) or chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) on voltage-dependent Na⁺ channels were compared. Bathing human myoballs in CSF substantially reduced their Na⁺ currents (by >40% with 8 of 10 patients) elicited at 1 Hz under whole-cell recording conditions. This was because, at the resting potential, more Na⁺ channels were inactivated (left-shift of the h_∞ curve). CSF from patients with other neurological diseases (OND) produces a similar, but smaller, effect. In contrast, serum samples from the same GBS and OND patients caused an increase of the Na⁺ currents by reducing the number of Na⁺ channels inactivated at the resting potential. This right-shift of the h_∞ curve is in part explained by the effect of serum albumin. We confirm that the CSF of most GBS and CIDP patients contains factors inhibiting voltage-dependent Na⁺ currents. There is no indication that such factors are effective in the serum of these patients. © 1995 John Wiley & Sons, Inc.     

Correlation of nerve ultrasound,electrophysiological, and clinical findings in post Guillain‐Barré syndrome

We aimed to correlate functional disability, electrophysiology, and nerve ultrasound in patients after Guillain‐Barré syndrome (GBS). Seventy‐five healthy controls and 41 post‐GBS patients (mean 3.4 years, SD ± 2.91 years after onset) underwent clinical, sonographic, and electrophysiological evaluation. Compared to healthy controls, the post‐GBS patients showed: (1) a mean Rasch‐built Overall Disability Scale score of 31.8 (SD ± 11.6), modified Rasch‐built fatigue severity scale score of 15.6 (SD ± 3.2), Medical Research Council sum score of 22 (SD ± 5.6); (2) electrophysiological signs of permanent axonal loss in the majority of the peripheral nerves; (3) sonographical evidence of higher cross‐sectional area values (CSA) of the ulnar (elbow, p < 0.001), radial (spiral groove, p < 0.001), tibial nerve (popliteal fossa, p < 0.001) and brachial plexus (supraclavicular space, p < 0.001). No correlation between sonographic and electrophysiological findings was found. Neither nerve ultrasound nor electrophysiology correlated with muscle strength, overall disability, and fatigue scale. Compared to healthy controls, post‐GBS patients had significant functional disability. Despite significant abnormalities in both electrophysiology and ultrasound compared to healthy controls, neither electrophysiology nor nerve ultrasound correlated with functional disability of these patients.     

Peripheral neuropathy and monoclonal IgM with antibody activity against peripheral nerve myelin; Effect of plasma exchange

Serum IgM antibodies directed against peripheral nerve myelin were demonstrated using enzyme-linked immunosorbent assay, mixed haemagglutination and indirect immunofluorescence in 3 patients with chronic polyneuropathy and monoclonal serum IgM. Isoelectric focusing followed by antigen immunofixation and autoradiography showed that the antimyelin antibodies co-migrated with the monoclonal IgM. Plasma exchange alone, without chemotherapy, proved beneficial in 2 patients. In one patient, plasma exchange was discontinued because of low IgG levels. Serum IgM and antimyelin antibodies decreased during plasma exchange and no increase beyond initial levels was noted after cessation of treatment.     

Electromyographic findings in patients after recovery from peripheral nerve lesions and poliomyelitis

Electromyography was performed in 10 patients 14 to 50 years after acute poliomyelitis and in 12 patients 6 to 16 years after a peripheral nerve lesion. All patients had made an almost complete recovery from initially severe paresis. In the poliomyelitis group the main finding was an increased mean action potential duration in all patients. In the patients with peripheral nerve lesions an increased frequency of spontaneous activity could be seen in 8 out of 10 and an increased mean action potential duration in 7 out of 9 patients during the initial phase. Six to 16 years later the main pathological results were a prolonged mean action potential duration (9 out of 12 patients) whilst increased spontaneous activity was detectable only in 3 of 12 patients. In two patients all EMG findings were normal.

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Zusammenfassung Zehn Patienten, die vor 14 bis 50 Jahren eine Poliomyelitis durchgemacht haben, und 12 Patienten mit einer peripheren Nervenläsion vor 6 bis 16 Jahren sind elektromyographisch untersucht worden. Alle Patienten hatten initial schwere Paresen, die weitgehend geheilt sind. Bei den Patienten mit Poliomyelitis war eine verlängerte mittlere Potentialdauer der wichtigste Befund. Bei den Patienten mit peripheren Nervenläsionen war vermehrte Spontanaktivität und eine verlängerte mittlere Potentialdauer in 8 von 10 bzw. in 7 von 9 Fällen initial gefunden worden. Bei den Nachuntersuchungen war eine verlängerte Potentialdauer ebenfalls der wichtigste Befund (9 von 12 Patienten). Vermehrte Spontanaktivität fand sich nur in 3 von 12 Fällen. Bei 2 Patienten waren alle EMG-Befunde normal.

     

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.     

皮肤神经活检与神经电生理以及腓肠神经活检的初步对比观察

目的 对周围神经病的患者进行皮肤神经活检、临床特点、神经电生理和腓肠神经活检的对比观察。方法 观察7例周围神经病患者，进行皮肤神经活检、腓肠神经活检、神经电生理检查，并对这些检查的一致性进行比较。结果 7例患者的神经电生理检查均提示有周围神经损害，腓肠神经活检也有不同程度的神经病变。6例皮肤神经活检同时有远近端皮肤神经的异常，且与腓肠神经活检所见病变的严重程度相一致。此6例患者的皮肤神经异常远端重于近端，符合长度依赖性周围神经病变。结论 皮肤神经活检与临床特点、神经电生理以及腓肠神经活检的结果有高度一致性；皮肤神经活检可以反映长度依赖性周围神经病变。     

Acute‐onset chronic inflammatory demyelinating polyneuropathy with cranial nerve involvement,dysautonomia, respiratory failure,and autoantibodies

We examined a 27‐year‐old woman who developed rapidly progressive quadriplegia and acute respiratory failure that required mechanical ventilation in the intensive care unit. It was unclear whether this was a presentation of Guillain–Barré syndrome (GBS) or acute‐onset chronic inflammatory demyelinating polyradiculoneuropathy (A‐CIDP). Remarkable features included multiple cranial nerve involvement, respiratory failure, dysautonomia, and skin manifestations. Several autoantibodies were elevated, including antinuclear (ANA), anticardiolipin (aCL), thyroid, and calcium‐sensing receptor (CaSR) autoantibodies. The patient was initially diagnosed with GBS and treated with intravenous immunoglobulin (IVIg). After almost complete recovery, relapse with quadriplegia and respiratory failure was observed 12 weeks after motor symptom onset. She then received IVIg and steroid pulse therapy followed by maintenance oral methylprednisolone and plasma exchange. She recovered completely 4 months after the relapse. The further clinical and serological course was consistent with systemic lupus erythematosus (SLE)‐associated CIDP. Herein we evaluate the association between A‐CIDP and some biological markers of autoimmunity. Muscle Nerve, 2010