R van Koningsveld

Effect of methylprednisolone when added to standard treatment with intravenous immunoglobulin for Guillain-Barré syndrome: Randomised trial

BACKGROUND Despite available treatment with intravenous immunoglobulin (IVIg), morbidity and mortality are considerable in patients with Guillain-Barré syndrome (GBS). Our aim was to assess whether methylprednisolone, when taken with IVIg, improves outcome when compared with IVIg alone. METHODS We did a double-blind, placebo-controlled, multicentre, randomised study, to which we enrolled patients who were unable to walk independently and who had been treated within 14 days after onset of weakness with IVIg (0.4 g/kg bodyweight per day) for 5 days. We assigned 233 individuals to receive either intravenous methylprednisolone (500 mg per day; n=116) or placebo (n=117) for 5 days within 48 h of administration of first dose of IVIg. Because age is an important prognostic factor, we split treatment groups into two age-groups-ie, younger than age 50 years, or 50 years and older. Our primary outcome was an improvement from baseline in GBS disability score of one or more grades 4 weeks after randomisation. Analysis was by intention to treat. FINDINGS We analysed 225 patients. GBS disability scores increased by one grade or more in 68% (76 of 112) of patients in the methylprednisolone group and in 56% (63 of 113) of controls (odds ratio [OR] 1.68, 95% CI 0.97-2.88; p=0.06). After adjustment for age and degree of disability at entry, treatment OR was 1.89 (95% CI 1.07-3.35; p=0.03). Side-effects did not differ greatly between groups. INTERPRETATION We noted no significant difference between treatment with methylprednisolone and IVIg and IVIg alone. Because of the relevance of prognostic factors and the limited side-effects of methylprednisolone, the potential importance of combination treatment with the drug and IVIg, however, warrants further investigation.

Measuring vibration threshold with a graduated tuning fork in normal aging and in patients with polyneuropathy. European Inflammatory Neuropathy Cause and Treatment (INCAT) group.

OBJECTIVE To provide clinically useful vibration threshold normal values. METHODS The graduated Rydel-Seiffer tuning fork was evaluated in 198 healthy controls and 59 patients with a polyneuropathy. The measures were done in triplicate at four locations: the distal interphalangeal joint of the index finger, ulnar styloid process, interphalangeal joint of the hallux, and internal malleolus. The values obtained with this tuning fork in healthy controls and patients with polyneuropathy were compared with the values of an electronic device, the Vibrameter. RESULTS Vibration sense was better perceived in the arms compared with the legs. There was a significant age related decline of vibration sense at all locations. The values from the Rydel-Seiffer tuning fork and the Vibrameter were significantly correlated in both groups. The sensitivity of these two instruments for the four sites examined in the polyneuropathy group ranged from 29–76% and 31–73%, respectively and was the highest at the hallux for both instruments. CONCLUSION This study provides clinical useful normal values of vibration threshold for the Rydel-Seiffer tuning fork. This is a simple and easily applicable instrument that assesses vibration sense semiquantitatively and should therefore have a place in routine neurological examination.

Mild forms of Guillain-Barré syndrome in an epidemiologic survey in the Netherlands

Objective: Assessment of incidence rates of Guillain-Barré syndrome (GBS) in the Netherlands over a 10-year period; investigation of a relationship between possible seasonality in GBS and the occurrence of preceding infections; and determination of distinctive characteristics in patients with GBS who are only mildly affected (able to walk unaided at nadir). Method: Records of patients with GBS admitted between 1987 and 1996 from all 45 hospitals in the southwest Netherlands were evaluated, covering a population of 4.2 million inhabitants. Results: A total of 476 patients met National Institute for Neurological and Communicative Disorders and Stroke criteria for GBS. This resulted in a crude incidence rate (IR) of 1.18/100,000 inhabitants. This IR increased linearly with age (p < 0.001). Men were more frequently affected than women (p < 0.001). No seasonal preponderance for GBS, nor for any of the preceding infections, was found. Patients under 50 years of age (p < 0.001) and men (p = 0.01) were more frequently found in the mildly affected group. In both groups a preceding infection was reported in 70% of the cases. In the severely affected group, serologic evidence for infection with Campylobacter jejuni, cytomegalovirus, Epstein–Barr virus, or Mycoplasma pneumoniae was found more frequently than in the mildly affected group (41% versus 16%, p = 0.001). Conclusions: Overall IR in the Netherlands are similar to those found in other studies. The incidence increases linearly with age and men are more frequently affected than women. Distinctive characteristics for mildly and severely affected patients were found regarding age, sex, and preceding infections. This suggests that other infectious agents or host factors may be involved in mild forms of GBS.

Health burden in the Netherlands due to infection with thermophilic Campylobacter spp.

Infection with thermophilic Campylobacter spp. usually leads to an episode of acute gastroenteritis. Occasionally, more severe diseases may be induced, notably Guillain Barré syndrome and reactive arthritis. For some, the disease may be fatal. We have integrated available data in one public health measure, the Disability Adjusted Life Year (DALY). DALYs are the sum of Years of Life Lost by premature mortality and Years Lived with Disability, weighted with a factor between 0 and 1 for the severity of illness. The mean health burden of campylobacter-associated illness in the Dutch population in the period 1990-5 is estimated as 1400 (90% CI 900-2000) DALY per year. The main determinants of health burden are acute gastroenteritis (440 DALY), gastroenteritis related mortality (310 DALY) and residual symptoms of Guillain-Barré syndrome (340 DALY). Sensitivity analysis demonstrated that alternative model assumptions produced results in the above-mentioned range.

IgG receptor IIa alleles determine susceptibility and severity of Guillain-Barré syndrome

Objective: Guillain-Barré syndrome (GBS) is characterized by nerve infiltration of leukocytes and autoantibodies of the immunoglobulin G (IgG) isotype directed against nerve constituents. Leukocyte receptors for IgG (FcγR) constitute an important link between the humoral and cellular parts of the immune system and confer potent cellular effector functions to myelin-directed antibodies. Three FcγR subclasses exhibit genetically determined biallelic functional polymorphisms (FcγRIIa: R131 versus H131; FcγRIIIa: 158V versus 158F; FcγRIIIb: NA1 versus NA2) that determine efficacy of the cellular immune response. To study the relevance of these polymorphisms for susceptibility and severity of GBS, we compared FcγR genotype distributions in GBS patients with those in controls. Methods: Genomic DNA was isolated from whole blood of 31 randomly selected patients with GBS and 187 healthy blood donors. Genotypes of the three polymorphic FcγR genes were determined by PCR. Results: FcγRIIa-H131 homozygosity was significantly increased in patients as compared with healthy controls (OR 2.45; 95% CI 1.12 to 5.36; p = 0.037). Furthermore, FcγRIIa-H131 homozygous GBS patients had a higher risk for severe disease than did patients with other genotypes (OR 18.57; 95% CI 1.95 to 176.49; p = 0.007). Conclusion: FcγRIIa allotypes capable of initiating efficient cellular effector functions are associated with increased risk for GBS and a more severe disease course. FcγR alleles may constitute novel genetic risk markers for GBS.

HLA class II alleles are not a general susceptibility factor in Guillain–Barré syndrome

Objective: To assess whether human leukocyte antigen (HLA)–DRB1 and HLA-DQB1 alleles confer susceptibility to Guillain-Barré syndrome (GBS) or are related to specific clinical or serologic subgroups of GBS. Methods: The HLA-DRB1 and HLA-DQB1 loci were genotyped by PCR amplification with sequence-specific primers in 164 well-documented Dutch patients with GBS and 207 healthy Dutch control subjects. Patients with GBS were divided into subgroups based on clinical features, severity of disease, antecedent infection, and anti-ganglioside antibodies. Data were compared with those of all case-control HLA studies in GBS performed previously. Results: In this case-control study, HLA-DRB1 and HLA-DQB1 alleles did not differ between GBS patients and control subjects. The frequency of HLA-DRB1*01 was increased in patients who needed mechanical ventilation (odds ratio 4.2; 95% CI 1.9 to 9.6; pc = 0.02). Multivariate logistic regression analysis showed that this association was independent of the severity of paresis and the presence of cranial nerve involvement (all p < 0.05). There was a tendency toward an association between certain HLA alleles and several anti-ganglioside antibodies. Conclusions: Human leukocyte antigen (HLA) class II antigens are not a general susceptibility factor in Guillain-Barré syndrome (GBS). However, HLA class II alleles may be a determinant in distinct subgroups of GBS, indicating the need for further exploration in large-scale studies.

Infections and course of disease in mild forms of Guillain–Barré syndrome

ObjectiveTwenty-eight percent of patients with the Guillain–Barré syndrome remain able to walk unaided. Studying patients with the mild form of Guillain–Barré syndrome can further contribute to knowledge of the spectrum of the syndrome and explore whether this subgroup may need treatment with IV immunoglobulin. MethodsPatients fulfilling the National Institute of Neurologic and Communicative Disorders and Stroke criteria for Guillain–Barré syndrome were included in a nationwide survey over a 2-year period. Clinical characteristics and serum samples were collected prospectively. In addition, a questionnaire was completed concerning the course and outcome of the disease. ResultsA total of 139 patients were included. Nineteen of the patients (14%) included were mildly affected, and 120 (86%) were severely affected. Infections with Epstein–Barr virus were found more frequently in mildly affected patients (p = 0.02). Antiganglioside antibodies were less frequently found in the mildly affected patients (p = 0.03). The degree of severity of the disease between mildly and severely affected patients was different on the day of admission (p < 0.01). Thereafter, the groups showed a remarkably similar rate of progression. Thirty-eight percent of mildly affected patients report problems in hand function and an inability to run at 3 and 6 months (all women, p = 0.02). ConclusionThe difference in severity of Guillain–Barré syndrome seems to be determined in an early phase of the disease. Preceding infections and antiganglioside antibodies may influence the initial immune attack, determining the severity of the disease. The presence of residual signs in patients with mild disease may advocate the use of early treatment in mildly affected patients.

Cross-reactive anti-galactocerebroside antibodies and Mycoplasma pneumoniae infections in Guillain–Barré syndrome

Anti-galactocerebroside (GalC) antibodies are reported to be present in GBS patients with preceding Mycoplasma pneumoniae (MP) infection. We investigated the presence of anti-GalC reactivity in serum of a large group of GBS patients using ELISA and compared this with healthy controls and individuals with an uncomplicated MP infection. Anti-GalC antibody reactivity was present in 12% of the GBS patients. Furthermore, anti-GalC antibodies were associated with MP infections, a relatively mild form of the disease and demyelinating features. Anti-GalC antibodies cross-reacted with MP antigen. In conclusion, anti-GalC antibodies in GBS patients may be induced by molecular mimicry with MP.

Gastroenteritis-associated Guillain–Barré syndrome on the Caribbean Island Curaçao

Background: The number of patients with Guillain–Barré syndrome (GBS) who have been observed in Curaçao, the Netherlands Antilles, may be increasing. Methods: Clinical and serologic data were obtained from records of patients admitted between 1987 and 1999 and fulfilling National Institute of Neurological and Communicative Disorders and Stroke criteria for GBS. When possible, serum and stool samples were collected. The results were compared with a large Dutch epidemiologic study. Results: The authors identified 49 patients, an overall crude incidence rate (IR) in Curaçao of 2.53/100,000 inhabitants (95% CI 1.87 to 3.35) (Dutch study 1.18, rate ratio (RR) of 2.14, p < 0.001). The IR in Curaçao increased from 1.62 in 1987 to 1991 to 3.10 in 1992 to 1999, RR 5.22 (95% CI 2.48 to 10.2, p = 0.02). The IR showed a curvilinear shape within a year. In comparison with the Dutch group, patients from Curaçao had a more severe course of the disease, with a mortality rate of 23% (3.4% in the Dutch group, p < 0.001), a higher percentage of preceding gastroenteritis (p < 0.001), and less sensory involvement (p < 0.001). In 8 of 10 serum samples, evidence was found for a recent infection with Campylobacter jejuni. Conclusions: The authors found a steady increase in incidence of GBS over the years in association with a more pronounced seasonal preponderance and a more severe course. The clinical characteristics suggest a role for C jejuni.

Treatment of Guillain–Barré syndrome with mycophenolate mofetil: a pilot study

Guillain–Barre syndrome (GBS) is a severe, acute, immune mediated polyneuropathy. Intravenous immunoglobulin (IVIg) is the preferred treatment.1 The combination of methylprednisolone (MP) and IVIg does not provide significantly better improvement after 4 weeks if not adjusted for important prognostic factors.2 GBS is associated with many longlasting residual deficits. Autoantibodies, and B and T cells are likely to play a role in the different stages of GBS.3 Mycophenolate mofetil (MM) is a relatively new immune suppressive agent, suppressing mainly B and T lymphocytes, and is thought to be of additional value in immune mediated neurological conditions.4–6 We conducted an open label pilot study to assess the additional effect of MM, administered simultaneously with IVIg and MP. The aim was to investigate whether additional treatment with MM is safe in patients with GBS and, secondly, whether there is a tendency to improved outcome. The study was approved by the ethics committees of Erasmus Medical Centre and the nine participating centres. All patients fulfilled the criteria for GBS.7 Eligibility criteria were onset of weakness within 2 weeks before inclusion and inability to walk independently for 10 m (GBS disability score ⩾3). Exclusion criteria were age less than 18 years, GBS in the past, pregnancy, breast feeding, immunosuppressive treatment, antacids treatment, use of drugs interfering with the enterohepatic recirculation, suffering from immune mediated disease other than well regulated diabetes mellitus and severe concurrent disease.2 The group of patients treated with IVIg and MP in the Dutch IVIg-MP trial was used as the historical control group. …