CSF Findings in Relation to Clinical Characteristics, Subtype, and Disease Course in Patients With Guillain-Barré Syndrome.

BACKGROUND AND OBJECTIVES: To investigate CSF findings in relation to clinical and electrodiagnostic subtypes, severity, and outcome of Guillain-Barré syndrome (GBS) based on 1,500 patients in the International GBS Outcome Study. METHODS: Albuminocytologic dissociation (ACD) was defined as an increased protein level (>0.45 g/L) in the absence of elevated white cell count (<50 cells/µL). We excluded 124 (8%) patients because of other diagnoses, protocol violation, or insufficient data. The CSF was examined in 1,231 patients (89%). RESULTS: In 846 (70%) patients, CSF examination showed ACD, which increased with time from weakness onset: ≤4 days 57%, >4 days 84%. High CSF protein levels were associated with a demyelinating subtype, proximal or global muscle weakness, and a reduced likelihood of being able to run at week 2 (odds ratio [OR] 0.42, 95% CI 0.25-0.70; p = 0.001) and week 4 (OR 0.44, 95% CI 0.27-0.72; p = 0.001). Patients with the Miller Fisher syndrome, distal predominant weakness, and normal or equivocal nerve conduction studies were more likely to have lower CSF protein levels. CSF cell count was <5 cells/µL in 1,005 patients (83%), 5-49 cells/µL in 200 patients (16%), and ≥50 cells/µL in 13 patients (1%). DISCUSSION: ACD is a common finding in GBS, but normal protein levels do not exclude this diagnosis. High CSF protein level is associated with an early severe disease course and a demyelinating subtype. Elevated CSF cell count, rarely ≥50 cells/µL, is compatible with GBS after a thorough exclusion of alternative diagnoses. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that CSF ACD (defined by the Brighton Collaboration) is common in patients with GBS.

An International Perspective on Preceding Infections in Guillain-Barré Syndrome: The IGOS-1000 Cohort.

BACKGROUND AND OBJECTIVES: Infections play a key role in the development of Guillain-Barré syndrome (GBS) and have been associated with specific clinical features and disease severity. The clinical variation of GBS across geographical regions has been suggested to be related to differences in the distribution of preceding infections, but this has not been studied on a large scale. METHODS: We analyzed the first 1,000 patients included in the International GBS Outcome Study with available biosamples (n = 768) for the presence of a recent infection with Campylobacter jejuni, hepatitis E virus, Mycoplasma pneumoniae, cytomegalovirus, and Epstein-Barr virus. RESULTS: Serologic evidence of a recent infection with C. jejuni was found in 228 (30%), M. pneumoniae in 77 (10%), hepatitis E virus in 23 (3%), cytomegalovirus in 30 (4%), and Epstein-Barr virus in 7 (1%) patients. Evidence of more than 1 recent infection was found in 49 (6%) of these patients. Symptoms of antecedent infections were reported in 556 patients (72%), and this proportion did not significantly differ between those testing positive or negative for a recent infection. The proportions of infections were similar across continents. The sensorimotor variant and the demyelinating electrophysiologic subtype were most frequent across all infection groups, although proportions were significantly higher in patients with a cytomegalovirus and significantly lower in those with a C. jejuni infection. C. jejuni-positive patients were more severely affected, indicated by a lower Medical Research Council sum score at nadir (p = 0.004) and a longer time to regain the ability to walk independently (p = 0.005). The pure motor variant and axonal electrophysiologic subtype were more frequent in Asian compared with American or European C. jejuni-positive patients (p < 0.001, resp. p = 0.001). Time to nadir was longer in the cytomegalovirus-positive patients (p = 0.004). DISCUSSION: Across geographical regions, the distribution of infections was similar, but the association between infection and clinical phenotype differed. A mismatch between symptom reporting and serologic results and the high frequency of coinfections demonstrate the importance of broad serologic testing in identifying the most likely infectious trigger. The association between infections and outcome indicates their value for future prognostic models.

Predicting Outcome in Guillain-Barré Syndrome: International Validation of the Modified Erasmus GBS Outcome Score.

BACKGROUND AND OBJECTIVES: The clinical course and outcome of the Guillain-Barré syndrome (GBS) are diverse and vary among regions. The modified Erasmus GBS Outcome Score (mEGOS), developed with data from Dutch patients, is a clinical model that predicts the risk of walking inability in patients with GBS. The study objective was to validate the mEGOS in the International GBS Outcome Study (IGOS) cohort and to improve its performance and region specificity. METHODS: We used prospective data from the first 1,500 patients included in IGOS, aged ≥6 years and unable to walk independently. We evaluated whether the mEGOS at entry and week 1 could predict the inability to walk unaided at 4 and 26 weeks in the full cohort and in regional subgroups, using 2 measures for model performance: (1) discrimination: area under the receiver operating characteristic curve (AUC) and (2) calibration: observed vs predicted probability of being unable to walk independently. To improve the model predictions, we recalibrated the model containing the overall mEGOS score, without changing the individual predictive factors. Finally, we assessed the predictive ability of the individual factors. RESULTS: For validation of mEGOS at entry, 809 patients were eligible (Europe/North America [n = 677], Asia [n = 76], other [n = 56]), and 671 for validation of mEGOS at week 1 (Europe/North America [n = 563], Asia [n = 65], other [n = 43]). AUC values were >0.7 in all regional subgroups. In the Europe/North America subgroup, observed outcomes were worse than predicted; in Asia, observed outcomes were better than predicted. Recalibration improved model accuracy and enabled the development of a region-specific version for Europe/North America (mEGOS-Eu/NA). Similar to the original mEGOS, severe limb weakness and higher age were the predominant predictors of poor outcome in the IGOS cohort. DISCUSSION: mEGOS is a validated tool to predict the inability to walk unaided at 4 and 26 weeks in patients with GBS, also in countries outside the Netherlands. We developed a region-specific version of mEGOS for patients from Europe/North America. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the mEGOS accurately predicts the inability to walk unaided at 4 and 26 weeks in patients with GBS. TRIAL REGISTRATION INFORMATION: NCT01582763.

Second intravenous immunoglobulin dose in patients with Guillain-Barré syndrome with poor prognosis (SID-GBS): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Treatment with one standard dose (2 g/kg) of intravenous immunoglobulin is insufficient in a proportion of patients with severe Guillain-Barré syndrome. Worldwide, around 25% of patients severely affected with the syndrome are given a second intravenous immunoglobulin dose (SID), although it has not been proven effective. We aimed to investigate whether a SID is effective in patients with Guillain-Barré syndrome with a predicted poor outcome. METHODS: In this randomised, double-blind, placebo-controlled trial (SID-GBS), we included patients (≥12 years) with Guillain-Barré syndrome admitted to one of 59 participating hospitals in the Netherlands. Patients were included on the first day of standard intravenous immunoglobulin treatment (2 g/kg over 5 days). Only patients with a poor prognosis (score of ≥6) according to the modified Erasmus Guillain-Barré syndrome Outcome Score were randomly assigned, via block randomisation stratified by centre, to SID (2 g/kg over 5 days) or to placebo, 7-9 days after inclusion. Patients, outcome adjudicators, monitors, and the steering committee were masked to treatment allocation. The primary outcome measure was the Guillain-Barré syndrome disability score 4 weeks after inclusion. All patients in whom allocated trial medication was started were included in the modified intention-to-treat analysis. This study is registered with the Netherlands Trial Register, NTR 2224/NL2107. FINDINGS: Between Feb 16, 2010, and June 5, 2018, 327 of 339 patients assessed for eligibility were included. 112 had a poor prognosis. Of those, 93 patients with a poor prognosis were included in the modified intention-to-treat analysis: 49 (53%) received SID and 44 (47%) received placebo. The adjusted common odds ratio for improvement on the Guillain-Barré syndrome disability score at 4 weeks was 1·4 (95% CI 0·6-3·3; p=0·45). Patients given SID had more serious adverse events (35% vs 16% in the first 30 days), including thromboembolic events, than those in the placebo group. Four patients died in the intervention group (13-24 weeks after randomisation). INTERPRETATION: Our study does not provide evidence that patients with Guillain-Barré syndrome with a poor prognosis benefit from a second intravenous immunoglobulin course; moreover, it entails a risk of serious adverse events. Therefore, a second intravenous immunoglobulin course should not be considered for treatment of Guillain-Barre syndrome because of a poor prognosis. The results indicate the need for treatment trials with other immune modulators in patients severely affected by Guillain-Barré syndrome. FUNDING: Prinses Beatrix Spierfonds and Sanquin Plasma Products.

Original research: Second IVIg course in Guillain-Barré syndrome with poor prognosis: the non-randomised ISID study.

OBJECTIVE: To compare disease course in patients with Guillain-Barré syndrome (GBS) with a poor prognosis who were treated with one or with two intravenous immunoglobulin (IVIg) courses. METHODS: From the International GBS Outcome Study, we selected patients whose modified Erasmus GBS Outcome Score at week 1 predicted a poor prognosis. We compared those treated with one IVIg course to those treated with two IVIg courses. The primary endpoint, the GBS disability scale at 4 weeks, was assessed with multivariable ordinal regression. RESULTS: Of 237 eligible patients, 199 patients received a single IVIg course. Twenty patients received an 'early' second IVIg course (1-2 weeks after start of the first IVIg course) and 18 patients a 'late' second IVIg course (2-4 weeks after start of IVIg). At baseline and 1 week, those receiving two IVIg courses were more disabled than those receiving one course. Compared with the one course group, the adjusted OR for a better GBS disability score at 4 weeks was 0.70 (95%CI 0.16 to 3.04) for the early group and 0.66 (95%CI 0.18 to 2.50) for the late group. The secondary endpoints were not in favour of a second IVIg course. CONCLUSIONS: This observational study did not show better outcomes after a second IVIg course in GBS with poor prognosis. The study was limited by small numbers and baseline imbalances. Lack of improvement was likely an incentive to start a second IVIg course. A prospective randomised trial is needed to evaluate whether a second IVIg course improves outcome in GBS.

Guillain-Barré syndrome in Denmark: a population-based study on epidemiology, diagnosis and clinical severity.

OBJECTIVES: To describe the epidemiology and clinical heterogeneity of Guillain-Barré syndrome (GBS) in Denmark and to compare a population-based cohort to prospectively included patients in the International GBS Outcome Study (IGOS). METHODS: The incidence rate (IR) of GBS in Denmark from September 2012 to December 2015, applying the National Institute of Neurological Disorders and Stroke (NINDS) diagnostic criteria, was estimated and the level of diagnostic certainty was described with the Brighton criteria. All cases registered with a diagnosis of GBS or other inflammatory neuropathies in the Danish National Hospital Registry were reviewed for diagnostic criteria and for information on treatment and clinical course. RESULTS: A total of 299 GBS cases were confirmed, corresponding to a crude IR of 1.59 (95% CI 1.42-1.78) per 100,000 per year. The Brighton criteria level 1-3 of diagnostic certainty was met in 279 (93%) of the patients. Thirty-five percent of the patients were mildly affected (GBS disability score < 3) and a correlation between high age and high disability score at nadir was found (Spearman's rank correlation coefficient 0.42, p < 0.0001). The group of 89 (30%) patients who were enrolled in IGOS had higher GBS disability score at nadir, were admitted 5 days earlier, reached nadir 4 days faster, and a larger proportion received treatment with IVIg (all p < 0.05). CONCLUSION: The epidemiology and full clinical spectrum of GBS are described in a population-based study. This includes a larger proportion of milder cases that are underrepresented in prospective cohorts such as IGOS.

Regional variation of Guillain-Barré syndrome.

Guillain-Barré syndrome is a heterogeneous disorder regarding the clinical presentation, electrophysiological subtype and outcome. Previous single country reports indicate that Guillain-Barré syndrome may differ among regions, but no systematic comparative studies have been conducted. Comparative studies are required to identify factors determining disease susceptibility, variation and prognosis, and to improve diagnostic criteria. The International Guillain-Barré Syndrome Outcome Study is a prospective, observational cohort study including all patients within the diagnostic spectrum, aiming to describe the heterogeneity of Guillain-Barré syndrome worldwide. The current study was based on the first 1000 inclusions with a follow-up of at least 1 year and confirmed the variation in clinical presentation, course and outcome between patients. The full clinical spectrum of Guillain-Barré syndrome was observed in patients from all countries participating in the International Guillain-Barré Syndrome Outcome Study, but the frequency of variants differed between regions. We compared three regions based on geography, income and previous reports of Guillain-Barré syndrome subtypes: 'Europe/Americas', 'Asia' (without Bangladesh), and 'Bangladesh'. We excluded 75 (8%) patients because of alternative diagnoses, protocol violations, or missing data. The predominant clinical variant was sensorimotor in Europe/Americas (n = 387/562, 69%) and Asia (n = 27/63, 43%), and pure motor in Bangladesh (n = 74/107, 69%). Miller Fisher syndrome and Miller Fisher-Guillain-Barré overlap syndrome were more common in Asia (n = 14/63, 22%) than in the other two regions (Europe/Americas: n = 64/562, 11%; Bangladesh: n = 1/107, 1%) (P < 0.001). The predominant electrophysiological subtype was demyelinating in all regions (Europe/Americas: n = 312/573, 55%; Asia: n = 29/65, 45%; Bangladesh: n = 38/94, 40%). The axonal subtype occurred more often in Bangladesh (n = 34/94, 36%) than in Europe/Americas (n = 33/573, 6%) and other Asian countries (n = 4/65, 6%) (P < 0.001). In all regions, patients with the axonal subtype were younger, had fewer sensory deficits, and showed a trend towards poorer recovery compared to patients with the demyelinating subtype. The proportion of patients able to walk unaided after 1 year varied between Asia (n = 31/34, 91%), Europe/Americas (n = 334/404, 83%) and Bangladesh (n = 67/97, 69%) (P = 0.003). A similar variation was seen for mortality, being higher in Bangladesh (n = 19/114, 17%) than in Europe/Americas (n = 23/486, 5%) and Asia (n = 1/45, 2%) (P < 0.001). This study showed that factors related to geography have a major influence on clinical phenotype, disease severity, electrophysiological subtype, and outcome of Guillain-Barré syndrome.

Clinical outcome of Guillain-Barré syndrome after prolonged mechanical ventilation.

BACKGROUND: Patients with Guillain-Barré syndrome (GBS) may suffer from respiratory failure for months or longer. The aim of this study was to determine the frequency, clinical course and outcome of patients with GBS requiring prolonged mechanical ventilation (MV). METHODS: Prospectively collected data from 526 patients with GBS participating in previous trials were analysed to determine the frequency and duration of prolonged MV (longer than 2 months). In addition, a cross-sectional study was conducted in patients with GBS requiring MV to determine the clinical course and long-term outcome with the ability to walk unaided as primary endpoint. RESULTS: In the cohort study, 145 of 526 patients with GBS (28%) required MV, including 33 (6%) patients with prolonged MV. Patients requiring prolonged MV had a lower Medical Research Council sum score and more frequent bulbar involvement and inexcitable nerves compared with shorter ventilated patients. At 6 months, 18% of patients with prolonged MV were able to walk unaided compared with 76% of patients requiring shorter MV (P<0.001). In the cross-sectional study, 63 patients requiring MV were included with a median follow-up of 11 years (range 2-44 years). Twenty-six (41%) of these patients needed prolonged MV (median 93 days, range 62-261). Fifteen (58%) of these patients were able to walk unaided at maximum follow-up and eight (31%) reached this endpoint more than 1 year after diagnosis. CONCLUSIONS: Prolonged ventilation in GBS is associated with poor prognosis, yet patients requiring prolonged ventilation may show slow but persistent recovery for years and even reach the ability to walk and live independently.

International Guillain-Barré Syndrome Outcome Study: protocol of a prospective observational cohort study on clinical and biological predictors of disease course and outcome in Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is an acute polyradiculoneuropathy with a highly variable clinical presentation, course, and outcome. The factors that determine the clinical variation of GBS are poorly understood which complicates the care and treatment of individual patients. The protocol of the ongoing International GBS Outcome Study (IGOS), a prospective, observational, multicenter cohort study that aims to identify the clinical and biological determinants and predictors of disease onset, subtype, course and outcome of GBS is presented here. Patients fulfilling the diagnostic criteria for GBS, regardless of age, disease severity, variant forms, or treatment, can participate if included within 2 weeks after onset of weakness. Information about demography, preceding infections, clinical features, diagnostic findings, treatment, course, and outcome is collected. In addition, cerebrospinal fluid and serial blood samples for serum and DNA is collected at standard time points. The original aim was to include at least 1,000 patients with a follow-up of 1-3 years. Data are collected via a web-based data entry system and stored anonymously. IGOS started in May 2012 and by January 2017 included more than 1,400 participants from 143 active centers in 19 countries across 5 continents. The IGOS data/biobank is available for research projects conducted by expertise groups focusing on specific topics including epidemiology, diagnostic criteria, clinimetrics, electrophysiology, antecedent events, antibodies, genetics, prognostic modeling, treatment effects, and long-term outcome of GBS. The IGOS will help to standardize the international collection of data and biosamples for future research of GBS.

Diagnosis of Guillain-Barré syndrome in children and validation of the Brighton criteria.

To describe the key diagnostic features of pediatric Guillain-Barré syndrome (GBS) and validate the Brighton criteria. Retrospective cohort study of all children (<18 years) diagnosed with GBS between 1987 and 2013 at Sophia Children's Hospital, Erasmus MC, Rotterdam. Clinical information was collected and the sensitivity of the Brighton criteria was calculated. 67 children (35 boys) were included, with a median age of 5.0 years [interquartile range (IQR) 3.0-10.0 years]. Bilateral limb weakness was present at hospital admission in 93% of children, and at nadir in all patients. Children presented with tetraparesis in 70% or with paraparesis in 23%. Reduced reflexes in paretic limbs were observed at hospital admission in 82% and during follow-up in all children. The progressive phase lasted median 6 days (IQR 3-8 days) and less than 4 weeks in all children. A monophasic disease course was seen in 97%, including 5 children with a treatment-related fluctuation. Two children had a later relapse at 9 weeks and 19 weeks after onset. 77% of the children showed an elevated protein level in CSF. Nerve conduction studies showed evidence for a poly(radiculo)neuropathy in 91% of the children. 46 children had a complete data set, the sensitivity of the Brighton criteria level 1 was 72% (95% CI 57-84) and 96% (95% CI 85-99) for level 2 and 98% (95% CI 88-100) for level 3. The majority of the pediatric GBS patients presented in this cohort fulfilled the current diagnostic criteria.

Innate Immunity to Campylobacter jejuni in Guillain-Barré Syndrome.

OBJECTIVE: Guillain-Barré syndrome (GBS) is a postinfectious neuropathy most frequently caused by Campylobacter jejuni. Lipo-oligosaccharides (LOS), expressed by C. jejuni induce antibodies that cross-react with self-glycolipids in peripheral nerves, causing neuropathy. Less than 1 in 1,000 persons infected with C. jejuni develop GBS, and the factors that determine GBS susceptibility are poorly understood. We hypothesized that these persons have a high intrinsic dendritic cell (DC) response to C. jejuni LOS through Toll-like receptor 4 (TLR4) activation. METHODS: Intrinsic DC responsiveness to C. jejuni LOS was investigated first in 20 healthy controls at three time points with a 3-month interval, and second in patients, who previously developed GBS after a C. jejuni infection (n = 27) and controls (n = 26). RESULTS: The DC response to C. jejuni LOS was highly variable between, but not within, healthy individuals, suggesting that intrinsic factors determine the magnitude of TLR4-mediated innate response. High responsiveness to C. jejuni LOS by former GBS patients was evidenced by increased expression of CD38 and CD40. Frequency of CD38, CD40 and type I interferon high responders was significantly increased in the GBS group. INTERPRETATION: These results suggest that a strong response to TLR4 stimulation is a critical host condition for the development of GBS after an infection with C. jejuni.

Guillain-Barré syndrome: pathogenesis, diagnosis, treatment and prognosis.

Guillain-Barré syndrome (GBS) is a potentially life-threatening postinfectious disease characterized by rapidly progressive, symmetrical weakness of the extremities. About 25% of patients develop respiratory insufficiency and many show signs of autonomic dysfunction. Diagnosis can usually be made on clinical grounds, but lumbar puncture and electrophysiological studies can help to substantiate the diagnosis and to differentiate demyelinating from axonal subtypes of GBS. Molecular mimicry of pathogen-borne antigens, leading to generation of crossreactive antibodies that also target gangliosides, is part of the pathogenesis of GBS; the subtype and severity of the syndrome are partly determined by the nature of the antecedent infection and specificity of such antibodies. Intravenous immunoglobulin and plasma exchange are proven effective treatments but many patients have considerable residual deficits. Discrimination of patients with treatment-related fluctuations from those with acute-onset chronic inflammatory demyelinating polyneuropathy is important, as these conditions may require different treatments. Novel prognostic models can accurately predict outcome and the need for artificial ventilation, which could aid the selection of patients with a poor prognosis for more-individualized care. This Review summarizes the clinical features of and diagnostic criteria for GBS, and discusses its pathogenesis, treatment and prognosis.

Paraparetic Guillain-Barré syndrome.

OBJECTIVE: To define the clinical and diagnostic characteristics of paraparetic Guillain-Barré syndrome (GBS) with weakness restricted to the legs, compared with the classic quadriparetic GBS. METHODS: Prospectively collected data from a cohort of 490 patients with GBS, previously involved in therapeutic or clinical studies, were used to define the demography, clinical presentation, diagnostic investigations, and clinical course in patients with paraparesis during a 6-month follow-up. RESULTS: Forty patients (8%) presented with a paraparesis without weakness of arms and hands. In 29 patients (73%), normal strength of upper extremities persisted during the follow-up period. Patients with paraparesis compared to patients with quadriparesis had a milder form of GBS, with less frequent cranial nerve involvement and less severe leg weakness, despite the fact that the majority of these patients were unable to walk unaided. Median time between onset of weakness and study entry was 6 days (interquartile range 4-11 days) for patients with paraparesis compared with 5 days (interquartile range 3-8 days) for patients with quadriparesis (p = 0.031). Fifty percent of patients with paraparesis presented with arm sensory deficits and 73% had reduced or absent arm reflexes. Nerve conduction studies demonstrated arm nerve involvement in 89% of these patients. At 6 months of follow-up, 98% of patients with paraparesis were able to walk unaided compared with 81% of the patients with quadriparesis (p = 0.008). There was no association between paraparesis and age, sex, or preceding infections. CONCLUSIONS: Paraparesis is an atypical clinical presentation or subform of GBS in which the diagnosis is usually supported by the presence of sensory deficits, reduced reflexes, or abnormal nerve conduction of the arms.

Guillain-Barré syndrome associated with preceding hepatitis E virus infection.

OBJECTIVE: The aim of the study was to determine whether Guillain-Barré syndrome (GBS) is associated with preceding hepatitis E virus infection. METHODS: The frequency of hepatitis E virus (HEV) infections was determined by anti-HEV serology in a cohort of 201 patients with GBS and 201 healthy controls with a similar distribution in age, sex, and year of sampling. Blood samples from patients with GBS were obtained in the acute phase before treatment. In a subgroup of patients with GBS, blood, stool, and CSF samples were tested for HEV RNA. RESULTS: An increased ratio of anti-HEV immunoglobulin (Ig) M antibodies was found in 10 patients with GBS (5.0%) compared with 1 healthy control (0.5%, odds ratio 10.5, 95% confidence interval 1.3-82.6, p = 0.026). HEV RNA was detected in blood from 3 of these patients and additionally in feces from 1 patient. Seventy percent of anti-HEV IgM-positive patients had mildly increased liver function tests. All CSF samples tested negative for HEV RNA. The presence of anti-HEV IgM in patients with GBS was not related to age, sex, disease severity, or clinical outcome after 6 months. CONCLUSIONS: In the Netherlands, 5% of patients with GBS have an associated acute HEV infection. Further research is required to determine whether HEV infections also precede GBS in other geographical areas.

Diagnosis of Guillain-Barré syndrome and validation of Brighton criteria.

Guillain-Barré syndrome is an acute polyradiculoneuropathy with a variable clinical presentation. Accurate diagnostic criteria are essential for patient care and research, including clinical trials and vaccine safety studies. Several diagnostic criteria for Guillain-Barré syndrome have been proposed, including the recent set by the Brighton Collaboration. In the present study we describe in detail the key diagnostic features required to meet these Brighton criteria in a study population of 494 adult patients with Guillain-Barré syndrome, previously included in therapeutic and observational studies. The patients had a median age of 53 years (interquartile range 36-66 years) and males slightly predominated (56%). All patients developed bilateral limb weakness which generally involved both upper and lower extremities. The weakness remained restricted to the legs in 6% and to the arms in 1% of the patients. Decreased reflexes in paretic arms or legs were found initially in 91% of patients and in all patients during follow-up. Ten (2%) patients however showed persistence of normal reflexes in paretic arms. Disease nadir was reached within 2 weeks in 80%, within 4 weeks in 97% and within 6 weeks in all patients. A monophasic disease course occurred in 95% of patients, of whom 10% had a treatment-related fluctuation. A clinical deterioration after 8 weeks of onset of weakness occurred in 23 (5%) patients. Cerebrospinal fluid was examined in 474 (96%) patients. A mild pleocytosis (5 to 50 cells/µl) was found in 15%, and none had more than 50 cells/µl. An increased cerebrospinal fluid protein concentration was found only in 64% of patients, highly dependent on the timing of the lumbar puncture after onset of weakness (49% at the first day to 88% after 2 weeks). Nerve electrophysiology was compatible with the presence of a neuropathy in 99% of patients, but only 59% fulfilled the current criteria for a distinct subtype of Guillain-Barré syndrome. Patients with a complete data set (335) were classified according to the Brighton criteria, ranging from a high to a low level of diagnostic certainty, as level 1 in 61%, level 2 in 33%, level 3 in none, and level 4 in 6% of patients. Patients categorized in these levels did not differ with respect to proportion of patients with preceding events, initial clinical manifestations or outcome. The observed variability in the key diagnostic features of Guillain-Barré syndrome in the current cohort study, can be used to improve the sensitivity of the diagnostic criteria.

Mortality in Guillain-Barre syndrome.

OBJECTIVE: To determine the frequency, timing, causes, and risk factors of death in Guillain-Barré syndrome (GBS). METHODS: Prospectively collected data were reviewed from a cohort of 527 patients with GBS previously included in 1 observational and 3 therapeutic studies. Risk factors were identified by comparing deceased and surviving patients with GBS. RESULTS: Fifteen (2.8%) of 527 patients with GBS died within 6 months of follow-up at highly variable time points during the disease course, with a median time from onset of weakness to death of 76 days (interquartile range 23-152 days). In 356 patients with an extended follow-up of 12 months, the mortality rate was 3.9%. Only 3 patients (20%) died during the acute progressive phase and 2 patients (13%) died during the plateau phase. Ten patients (67%) died during the recovery phase after neurologic improvement, most frequently from respiratory or cardiovascular complications. Eleven patients (73%) were admitted to an intensive care unit during the course of disease, but only 7 patients (47%) died in the intensive care unit. Risk factors for death were age (p < 0.001), severity of weakness at entry (p = 0.02), mechanical ventilation (p < 0.001), delay from onset of weakness to entry (p = 0.035), and time to peak disability (p = 0.039). CONCLUSIONS: Death after GBS predominantly occurs in the elderly and severely affected patients, especially during the recovery phase. Future research is required to determine whether mortality of GBS can be reduced by intensified monitoring in patients with an increased risk profile.

[Ocular myasthenia gravis: diagnosis often delayed]. / Oculaire myasthenia gravis. Diagnose vaak pas laat gesteld.

When a patient complains of a fluctuating ptosis or diplopia the diagnosis 'ocular myasthenia gravis' must be considered. The diagnosis can be difficult because of the subtle symptoms and less sensitive diagnostic testing. Because of this, there is often a patient and doctors delay. We describe 3 patients, a 63-year-old man, a 49-year-old woman and a 77-year-old woman, who received the right diagnosis only after 22 months, 4 months and even 9 years after the first symptom occurred. At the neurological examination the provocation tests are of high importance. Confirmation of the diagnosis can be established with the following diagnostic procedures: neostigmine test, serological testing for antibodies against acetylcholine receptors and single fibre EMG.