Prognostic factor of poor outcome in anti-MAG neuropathy: clinical and electrophysiological analysis of a French Cohort.

BACKGROUND: Anti-MAG polyneuropathy (anti-MAG PN) is an immune-mediated peripheral sensorimotor neuropathy characterized by distal demyelination and ataxia. However, this disorder, unlike other immune-mediated neuropathies, is difficult to treat in most cases. METHOD: We retrospectively collected all anti-MAG PN patients followed in two hospitals for a period of 12 years to determine prognostic factors, especially those that indicated a good response to the various therapeutic strategies used. RESULTS: Forty-seven patients were included in the study; of these, 61% had a classical 'distal demyelinating pattern', 34.2% had a 'CIDP-like pattern', and the others had an 'axonal pattern'. The most commonly used treatments were intravenous immunoglobulin (IVIg) as the first-line treatment and rituximab as the second- or third-line treatment. No prognostic factor was identified for IVIg, but electrophysiological parameters at onset were better in patients with a good response to rituximab than in non-responder patients, even though mild or high disability was observed in nearly half the patients at last examination. CONCLUSION: Even though disability seems to progress in most cases despite the treatments used, our results suggest that an early electrophysiological reduction in sensory nerves could be considered a 'red flag' for the prompt initiation of rituximab to try to delay long-term disability.

Nodo-paranodopathy, internodopathy and cleftopathy: Target-based reclassification of Guillain-Barré-like immune-mediated polyradiculoneuropathies in dogs and cats.

Recent views on Guillain-Barré syndrome (GBS) question the accuracy of classification into axonal and demyelinating subtypes that represent convergent neurophysiological phenotypes rather than immunological targets. Instead it has been proposed to clarify the primarily affected fibre subunit in nerve biopsies. As nerve biopsies rarely are part of routine work-up in human patients we evaluated tissues taken from companion animals affected by GBS-like polyradiculoneuropathy to screen for distribution of immune cells, targeted fibre components and segregating non-inflammatory lesions. We identified that immune responses were directed either at Schmidt-Lanterman clefts, the paranode-node complex or both. Based on infiltrative and non-inflammatory changes, four subtypes and/or stages were distinguished, some of which indicate localisation of primary target antigens while others represent convergent late stage pictures, as a consequence to epitope spreading. The impact of histological subtyping onto clinical management and prognosis remains to be evaluated in future clinical trials. Natural development and clinical manifestation of large animal dysimmune neuropathy may reflect human Guillain-Barré syndrome more accurately than experimental models and therefore provide complementary clues for translational research.

Glial fibrillary acidic protein as a marker of axonal damage in chronic neuropathies.

We evaluated serum glial fibrillary acidic protein (GFAP) levels by enzyme-linked immunosorbent assay (ELISA) in controls (n = 30) and in patients with chronic sensory-motor axonal neuropathy (CSMAN) (n = 30), chronic inflammatory demyelinating polyneuropathy (CIDP) (n = 30), multifocal motor neuropathy (MMN) (n = 30), and primary muscular spinal atrophy (PMSA) (n = 15). GFAP levels, expressed as optical density, were increased in CSMAN (median = 1.05) compared to controls (median = 0.41; P < 0.05) and CIDP (median = 0.53, P < 0.05). They were also increased in PMSA (median = 0.99) compared to controls (P < 0.05) and MMN (median = 0.66; P < 0.05). To differentiate CSMAN from CIDP and PMSA from MMN, we applied a cutoff of GFAP levels at 0.66, and we obtained good sensitivity and specificity. In neuropathies, serum GFAP correlated with summated sensory nerve action potential amplitudes (r = -0.57; P = 0.0006) and disease severity (r = 0.37; P = 0.0011). Thus, we propose serum GFAP as a marker of axonal damage and severity in chronic neuropathies.

Outcome measures in immune-mediated neuropathies: the need to standardize their use and to understand the clinimetric essentials.

Peripheral neurological disorders like neuropathies may cause impairments (such as weakness and sensory deficits), which may lead to problems in daily life and social functioning with a possible decrement in quality of life expectations. Choosing the proper outcome measure to evaluate the therapeutic efficacy of an intervention at one of these levels of outcome should therefore be considered as fundamental to the design of randomized trials in peripheral neurological disorders. However, these choices are dependent not only on the proposed research purposes but also, and perhaps more importantly, on the fulfillment of the scientific needs of these measures. With an increasing demand for accuracy, a thorough and comprehensive evaluation of an outcome measure is needed to determine its simplicity, communicability, validity, reliability, and responsiveness before being clinically applicable, techniques that are being captured by the science of clinimetrics. Most neurologists are still unfamiliar with these rigorous methodological essentials or overlook some of them in their trial preparations because these are considered time consuming and mind numbing. This review will highlight, against the background of the international classification framework and clinimetric needs for outcome measures, the selected scales applied in published randomized controlled trials in patients with Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, and gammopathy-related neuropathies. The need for comparison responsiveness studies between equally valid and reliable measures and to standardize their use is emphasized in these conditions. Finally, specific recommendations are given to move from classic to modern clinimetric approach when constructing, evaluating, and selecting outcome measures using new methods like Rasch analysis, accentuating the need of shifting toward a more modern era.

Classifications and treatment responses in chronic immune-mediated demyelinating polyneuropathy.

BACKGROUND: Chronic immune-mediated demyelinating polyneuropathy (CIP) represents a heterogeneous pool of motor, sensory, sensorimotor, symmetric, or asymmetric syndromes. OBJECTIVE: To evaluate published diagnostic classifications and characterize predictors of treatment response. METHODS: One hundred two of 158 patients with a working diagnosis of CIP were included and clinically characterized because they had electrophysiologic and/or histologic evidence of demyelination. The biostatistical profile of patients with symmetric clinical manifestation was analyzed using three proposed classifications (American Academy of Neurology [AAN] criteria, modified AAN criteria, European Federation of Neurological Societies/Peripheral Nerve Society [EFNS/PNS] criteria). Treatment responses to IV immunoglobulins (IVIg) and their positive predictors were investigated. RESULTS: Sensitivities (0.52 [AAN] vs 0.83 [modified AAN] vs 0.95 [EFNS/PNS]) and negative predictive values (0.68 vs 0.85 vs 0.92) differed markedly, whereas specificities (0.94 vs 0.90 vs 0.96) and positive predictive values (0.89 vs 0.89 vs 0.97) were similar. In CIP patients treated with IVIg, a positive response was found in 62 of 76 (82%). Patients with a monophasic or relapsing-remitting course or a more than twofold CSF protein increase had the highest probability to respond to IVIg, most evident when using the modified AAN criteria. CONCLUSIONS: The European Federation of Neurological Societies/Peripheral Nerve Society criteria for chronic inflammatory demyelinating polyneuropathy improve treatment of patients with chronic immune-mediated demyelinating polyneuropathy, particularly with respect to diagnostic issues. To predict IV immunoglobulin treatment response, the modified American Academy of Neurology criteria are the most valuable classification provided an increased CSF protein level.

[The extent of the clinical manifestations of chronic polyradiculoneuropathy]. / Les limites cliniques du concept de polyradiculonévrite chronique.

BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy is an autoimmune disease that target myelin sheats of peripheral nerves. Its diagnosis is often difficult to make, and a number of cases are probably not identified because of the clinical heterogeneity. Numerous sets of diagnostic criteria have sought to define CIDP but clinical criteria are generally not detailed. OBJECTIVES: To review the main clinical characteristics suggestive of CIDP (that means not compatible with a length-dependent axonal process) and the critical clinical points of the neuropathy which make the differential diagnosis with the main other forms of chronic auto immune neuropathy sometimes difficult. RESULTS: The main clinical characteristic are: a symmetric proximal and distal motor weakness predominantly affecting the lower limbs, a diffuse areflexia, a sensory deficit characterized by a preferential involvement of large fibers, an evolution which may be either chronic progressive or recurrent. These aspects raise many questions concerning overlap with other inflammatory neuropathies such as Guillain Barre syndrome, Lewis-Sumner neuropathy, chronic ataxic neuropathy. The distinction of a subgroup of CIDP associated with other diseases such as diabetes or HIV are also controversial. CONCLUSION: The growing body of knowledge on the pathogenesis of CIDP and clinical or electrophysiological differentiation of subforms may help to develop more effective therapies for CIDP in the next few years.

Subacute inflammatory demyelinating polyneuropathy in children.

Reported are five children with subacute demyelinating polyneuropathy. All patients had a monophasic disease, progressing over 4 to 8 weeks and characterized by predominantly motor features, areflexia, minimal or no cranial nerve abnormalities, no autonomic or respiratory involvement, elevated CSF protein, electrophysiologic evidence of demyelination, and good response to corticosteroids. A benign course with full recovery was the rule.

[Acquired dysimmune neuropathies. Clinical symptoms and classification]. / Neuropatías disinmunes adquiridas. Sintomatología clínica y clasificación.

INTRODUCTION: The neuropathies caused by dysimmunity have seen great changes in recent years. The different forms of clinical presentation, electrophysiological expression, associated anomalies seen on analytical tests, particularly the presence of antibodies to the various antigens of myelin are becoming better understood. This confirms their dysimmune nature and also offers unforeseen possibilities for the comprehension of etiopathogenic mechanisms and possible classifications of specific etiopathogenic factors. DEVELOPMENT: Based mainly on our own experience, in this paper we review current concepts of the three main dysimmune polyneuropathies, the Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuritis or CIDP and the motor multifocal neuropathies (MMN) with block-conduction or Lewis-Summer syndrome. Regarding the first condition, we particularly emphasize the convenience of establishing the broad classification needed by the variation in its clinical presentation, with regional and functional variants: among the latter we consider particularly the pure motor forms which in most cases are axonal forms with an etiopathogenic basis which is fairly well established and almost constantly associated with the presence of specific antibodies in the serum of patients with this condition. With reference to CIDP, we discuss the existence of atypical forms and the frequency of the relapsing form concerning the evolution. The MMN are the most recently discovered dysimmune neuropathies, according to both the literature and personal experience. We try to establish the difference between pure motor forms and those which also have sensory involvement (or MADSAM) and are called the Lewis-Sumner syndrome.

[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.

Síndrome de Guillain-Barré: revisión de aspectos clínicos y etiopatogénicos a propósito de un caso clínico / Guilleain-Barreïs syndrome: review of clinical and etiopathogenical aspects in relation to a clinical case

El síndrome de Guillain-Barré es una enfermedad poco frecuente en la cual el sistema nervioso periférico es infiltrado con linfocitos y macrófagos y la mielina es destruida. Su característica principal, secundaria al enlentecimiento de velocidad de conducción nerviosa, es el déficit motor. Más de la mitad de los casos ocurren en relación con una enfermedad infecciosa previa. Hay evidencias que sugieren que la patogenia involucra una reacción autoinmune de tejido nervioso periférico gatillada por la infección. El conocimiento de la patogenia es la base sobre la que se sustentan los procedimientos terapéuticos útiles como la plasmaféresis y el uso de inmunoglobulina endovenosa, cuya eficacia depende de la precocidad de su aplicación. Se comunica un caso clínico de síndrome de Guillain-Barré común a propósito del cual se revisan aspectos clínicos, etiopatogénicos y terapéuticos. La importancia del conocimiento de la génesis del daño no sólo tiene importancia teórica, sino también ha servido de base en la búsqueda e instauración de procedimientos terapéuticos específicos, además de los sintomáticos actualmente utilizados. Es el caso de la instauración de la plasmaféresis y de la administración de inmunoglobulina endovenosa en altas dosis como elementos útiles en la actualidad

Electrophysiological classification of Guillain-Barré syndrome: clinical associations and outcome. Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group.

We performed electrophysiological and serological testing within 15 days of symptom onset on 369 patients with Guillain-Barré Syndrome (GBS) enrolled in a trial comparing plasma exchange, intravenous immunoglobulin, and both treatments. Patients were classified into five groups by motor nerve conduction criteria; 69% were demyelinating, 3% axonal, 3% inexcitable, 2% normal, and 23% equivocal. Six of 10 (60%) patients with axonal neurophysiology had had a preceding diarrheal illness compared with 71 of 359 (20%) in other groups. Antiganglioside GM1 antibodies were present in a higher proportion of patients with axonal physiology or inexcitable nerves than other patients. The number dead or unable to walk unaided at 48 weeks was greater in the group with initially inexcitable nerves (6 of 12, 50%) compared with the rest (52 of 357, 15%), but was not significantly different between the axonal (1 of 10, 10%) and demyelinating (44 of 254, 17%) groups. Sensory action potentials and clinical sensory examination were both normal in 53 of 342 (16%) patients, and these "pure motor GBS" patients were more likely than other GBS patients to have IgG antiganglioside GM1 antibodies and to have had preceding diarrhea but had a similar outcome. The axonal group was more likely than other groups to have normal sensory action potentials. The outcomes in response to the three treatments did not differ in any subgroup (including patients with pure motor GBS or preceding diarrhea) or any neurophysiological category.

Electrophysiological studies in the Guillain-Barré syndrome: distinguishing subtypes by published criteria.

Guillain-Barré syndrome (GBS) is recognized clinically by the presence of acute, rapidly progressive weakness, areflexia, and albuminocytological dissociation in cerebrospinal fluid. Although GBS was initially considered to be primarily an acute inflammatory demyelinating polyneuropathy (AIDP), several other subtypes have been recognized: acute motor axonal neuropathy (AMAN), acute motor-sensory axonal neuropathy (AMSAN), and Fisher syndrome (FS). Because each of these subtypes may have an independent immunopathogenesis and, therefore, may require selective treatments in the future, recognition of these subtypes is important. When using nerve conductions to classify the subtypes, the most easily and confidently identified subtype is AIDP. Therefore, most electrodiagnostic criteria have attempted to identify demyelination in this acute setting, in which physiology is constantly changing. In a single well-defined GBS population, we compared the various published criteria for demyelination in GBS. We reviewed charts of 43 patients with GBS between 1991 and 1996. Applying six available criteria sets, the number of patients categorized as having AIDP ranged from 21% to 72%. Until investigators can agree on a single set of criteria, considerable variability will continue to exist when identifying cases of AIDP.

[A case of pharyngeal-cervical-branchial variant of Guillain-Barré syndrome with IgG anti-GT1a antibody].

A 36-year-old man with pharyngeal-cervical-brachial variant of Guillain-Barré syndrome (PCB) was described. Neurologic examination revealed total ophthalmoplegia, pharyngeal-cervical-brachial weakness and hyporeflexia in the upper limbs, sparing power and tendon reflexes in the lower limbs. Enzyme-linked immunosorbent assay showed that he had high titer of IgG antibody to GT1a (1:32,000), which did not cross-react with GQ1 b or GD1a. Thin-layer chromatography immunostaining confirmed that his serum IgG reacted with GT1a. These findings show that IgG anti-GT1a antibody without cross-reactivity with GQ1b plays a role in the development of PCB.

Guillain-Barré syndrome variants in Emilia-Romagna, Italy, 1992-3: incidence, clinical features, and prognosis. Emilia-Romagna Study Group on Clinical and Epidemiological Problems in Neurology.

OBJECTIVES: To estimate the incidence rate of Guillain-Barré syndrome variants in an unselected population and to describe their clinical features and prognosis. METHODS: A two year prospective multicentre study on the incidence and prognosis of Guillain-Barré syndrome was performed in Emilia-Romagna, northern Italy (3,909,512 inhabitants). A surveillance system was instituted within the study area, which comprised all the neurological departments, private and public general hospitals, and practising neurologists. The international classification of diseases (ICD) codes 357.XX (any peripheral neuropathy) of hospital discharges were also reviewed. RESULTS: Data were separately analysed for Miller Fisher syndrome and other Guillain-Barré syndrome variants. During the study period 18 patients with Guillain-Barré syndrome variants including seven with Miller Fisher syndrome were recruited; the incidence rates were 0.14/100000/year (95% confidence interval (95% CI) 0.07-0.25) for Guillain-Barré syndrome variants (excluding Miller Fisher syndrome) and 0.09/100000/year (95% CI 0.04-0.18) for Miller Fisher syndrome. Guillain-Barré syndrome variants alone (excluding Miller Fisher syndrome) accounted for 10.5% of total cases. Death and relapses were not found. Details of clinical, electrophysiological, and CSF findings of Guillain-Barré syndrome variants are provided. CONCLUSIONS: Guillain-Barré syndrome variants other than Miller Fisher syndrome, as obtained through a population based study, account for about 10% of total cases of Guillain-Barré syndrome and, as a whole, have a good prognosis. Their clinical features are heterogeneous; bifacial weakness (associated with other signs, mainly sensory disturbances) represents the most frequent finding.

Guillain-Barré syndrome: multifactorial mechanisms versus defined subgroups.

The clinical spectrum of Guillain-Barré syndrome (GBS) is summarized in relation to antecedent infections and anti-ganglioside antibodies. Associations exist between a pure motor form of GBS, diarrhea, Campylobacter jejuni infection, and anti-GM1 antibodies; between cranial nerve involvement and Miller Fisher syndrome, C. jejuni infection, and anti-GQ1b antibodies; and between variants, such as severe sensory involvement and cytomegalovirus infection. These three clinical variants are suggested to form the extremes of a continuous spectrum; they are discussed in relation to the more pathologically defined patterns of acute motor axonal neuropathy and acute motor-sensory axonal neuropathy. In particular, patients with a clinically pure motor variant of GBS, diarrhea, anti-GM1 antibodies, or C. jejuni infection seem to respond better to early treatment with high-dose immunoglobulins than to plasma exchange.