Hyponatraemia in Guillain-Barré syndrome revisited.

OBJECTIVES: The objective of this study was to determine the relevance of hyponatraemia in the prognosis of Guillain-Barré syndrome (GBS). MATERIALS AND METHODS: We retrospectively analysed records of 48 consecutive patients with GBS and performed a systematic literature review on frequency/correlates of hyponatraemia in GBS. RESULTS: Hyponatraemia <133 mmol/l was detected in 18/48 of our patients with GBS (37.5%). In 10/18 (55.5%), hyponatraemia occurred post-immunoglobulin therapy. Hyponatraemia correlated with age >50 years (P = 0.011), concurrent malignancy (P = 0.039), diuretic use (P < 0.001), preceding diarrhoea (P = 0.042) and Medical Research Council (MRC) sum score at discharge (MRCSSD) (P = 0.026). Only concurrent malignancy (P < 0.001) and diuretic use (P < 0.001) were independently associated with hyponatraemia. MRCSSD also correlated with MRC sum score on admission (MRCSSA) (P < 0.001), length of hospital stay (P < 0.001), summated compound muscle action potential (P = 0.034) and lowest forced vital capacity (P = 0.001). Only MRCSSA (P = 0.004) and length of hospital stay (P < 0.001) independently predicted MRCSSD. Combining our findings with previous literature indicates comparable frequencies of hyponatraemia in GBS in four of five studies and association with mortality in three of four studies, with an independent link in one. Independent association of hyponatraemia with muscle strength is not demonstrated. CONCLUSION: Hyponatraemia appears of comparable frequency in GBS to that in other diseased cohorts suggesting it is common but non-specific. Hyponatraemia has otherwise been shown to be an independent predictor of death in other disorders and available data indicate the same is also likely in GBS, although this may vary in patient subgroups. Hyponatraemia is, however, not an independent prognostic indicator of neuromuscular weakness severity in GBS.

An update in guillain-barré syndrome.

Guillain-Barré syndrome (GBS) was first described in 1916 (Guillain G, 1916) and is approaching its 100th anniversary. Our knowledge of the syndrome has hugely expanded since that time. Once originally considered to be only demyelinating in pathology we now recognise both axonal and demyelinating subtypes. Numerous triggering or antecedent events including infections are recognised and GBS is considered an immunological response to these. GBS is now considered to be a clinical syndrome of an acute inflammatory neuropathy encompassing a number of subtypes with evidence of different immunological mechanisms. Some of these are clearly understood while others remain to be fully elucidated. Complement fixing antibodies against peripheral nerve gangliosides alone and in combination are increasingly recognised as an important mechanism of nerve damage. New antibodies against other nerve antigens such as neurofascin have been recently described. Research databases have been set up to look at factors associated with prognosis and the influence of intravenous immunoglobulin (IvIg) pharmacokinetics in therapy. Exciting new studies are in progress to examine a possible role for complement inhibition in the treatment of the syndrome.

Guillain-Barré syndrome: clinical variants and their pathogenesis.

Numerous clinical subtypes of Guillain-Barré syndrome have been described over the century since the original description of the syndrome. These variants of Guillain-Barré syndrome are discussed and their immunological pathogenesis reviewed.

When the Guillain-Barre patient fails to respond to treatment.

Most patients with Guillain-Barré syndrome (GBS) respond to treatment with intravenous immunoglobulin, but it is not uncommon for some to continue to deteriorate for a period after treatment has been started. This may reflect the natural history of the disease, or an error in diagnosis. This article reflects my own view of what to do in this situation, with a review of what few data there are to guide decision making.

Sensory detection thresholds are modulated across the cardiac cycle: evidence that cutaneous sensibility is greatest for systolic stimulation.

The visceral afferent feedback hypothesis proposes that sensorimotor function is impaired by cortical inhibition associated with increased baroreceptor activation. This study is the first to examine the effects of naturally occurring variations in baroreceptor activity across the cardiac cycle on cutaneous sensory detection thresholds. In each trial, an electrocutaneous stimulus was delivered to the index finger at one of three intervals (0, 300, 600 ms) after the R-wave of the electrocardiogram. Separate interleaving up-down staircases were used to determine the 50% detection threshold for each R-wave to stimulation interval. Cutaneous sensory detection thresholds were lower for stimuli presented at R+300 ms than R+0 ms or R+600 ms. The finding that cutaneous sensibility was greater when stimulated during systole than diastole may be accounted for by a modified afferent feedback hypothesis.

Immunosuppressant and immunomodulatory treatment for dermatomyositis and polymyositis.

BACKGROUND: Idiopathic inflammatory myopathies are chronic skeletal diseases with significant mortality and morbidity despite treatment by corticosteroids. Immunosuppressive agents and immunomodulatory therapy are used to improve disease control and reduce the long-term side effects of corticosteroids. While these treatments are used commonly in routine clinical practice, the optimal therapeutic regimen remains unclear. OBJECTIVES: To systematically review the evidence for the effectiveness of immunosuppressants and immunomodulatory treatments for dermatomyositis and polymyositis. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register (searched February 2002 and updated in November 2003) and MEDLINE (January 1966 to December 2002). We checked bibliographies of identified trials and wrote to disease experts. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials including patients with probable or definite dermatomyositis and polymyositis as defined by the criteria of Bohan and Peter or definite, probable or mild/early by the criteria of Dalakas. Patients with inclusion body myositis should have been excluded by muscle biopsies. Any immunosuppressant or immunomodulatory treatment including corticosteroids, azathioprine, methotrexate, ciclosporin, chlorambucil, cyclophosphamide, intravenous immunoglobulin, interferon and plasma exchange was considered. Primary outcome was assessment of muscle strength after at least six months. Other outcomes were: change in disability, number of relapses and time to relapse, number of patients in remission and time-to-remission, cumulative corticosteroid dose and serious adverse effects. DATA COLLECTION AND ANALYSIS: Two authors (EC and JH) independently selected trials for inclusion in the review. Four authors independently assessed each study. Methodological criteria and the results of each study were recorded on data extraction forms. MAIN RESULTS: Seven potentially relevant randomised controlled trials were identified. One trial was excluded. Three studies compared immunosuppressant with placebo control, one trial compared one immunosuppressant (methotrexate) with another (azathioprine), another trial compared ciclosporin A with methotrexate and the final trial compared intramuscular methotrexate with oral methotrexate plus azathioprine. The study comparing intravenous immunoglobulin with placebo concluded that the former was superior. Two randomised placebo-controlled trials assessing plasma exchange, leukapheresis and azathioprine produced negative results. The fourth study compared azathioprine with methotrexate and found azathioprine and methotrexate equally effective but methotrexate had a better side effect profile. The fifth study comparing ciclosporin A with methotrexate and the sixth study comparing intramuscular methotrexate with oral methotrexate plus azathioprine found no statistically significant differences between the treatment groups. Immunosuppressants are associated with significant side effects. AUTHORS' CONCLUSIONS: This systematic review highlights the lack of high quality randomised controlled trials that assess the efficacy and toxicity of immunosuppressants in inflammatory myositis.

An interferon-gamma ELISPOT and immunohistochemical investigation of cytotoxic T lymphocyte-mediated tumour immunity in patients with paraneoplastic cerebellar degeneration and anti-Yo antibodies.

Eight patients with paraneoplastic cerebellar degeneration (PCD) and anti-Yo antibodies were investigated to determine whether there is any association between cytotoxic T lymphocyte (CTL) responses reactive with two previously defined Yo-derived, HLA-A2.1 restricted epitopes (cdr2-1 and cdr2-2) and the presence of tumour-infiltrating CD8+ CTLs. cdr2-1 and cdr2-2-specific CTL responses could not be detected in 5 HLA-A2.1(+) patients in an ex vivo interferon-gamma ELISPOT assay and only 2/9 tumour sections contained CD8(+) intratumoural lymphocytes suggesting a very limited role for CTL-mediated tumour immunity in this patient group, all of whom had evidence of widespread malignancy at the time of diagnosis and/or death.

A randomized controlled trial of recombinant interferon-beta 1a in Guillain-Barré syndrome.

The authors recruited 19 nonambulant patients with Guillain-Barré syndrome into a pilot, double-blind, randomized, placebo-controlled safety trial of interferon beta 1a (IFN[beta]-1a) (Rebif). Participants received IFN[beta]-1a or placebo subcutaneously three times weekly, 22 microg for the first week and then 44 microg for up to 24 weeks, in addition to IV immunoglobulin (IVIg). IFN[beta] did not have any unexpected interaction with IVIg and there was no significant difference in rate of improvement.

Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy is an immune mediated disorder characterised by progressive or relapsing symmetrical motor or sensory symptoms and signs in more than one limb, developing over at least two months. It may cause prolonged periods of disability and even death. Several uncontrolled studies have suggested a beneficial effect of intravenous immunoglobulin. OBJECTIVES: To review systematically the evidence from randomised controlled trials concerning the efficacy and safety of intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy. SEARCH STRATEGY: We used the Search Strategy of the Cochrane Neuromuscular Disease Review Group to search the Disease Group register and other databases for randomised controlled trials from 1985 onwards. SELECTION CRITERIA: Randomised controlled studies examining the effects of any dose of intravenous immunoglobulin versus placebo, plasma exchange or corticosteroids in patients with definite or probable chronic inflammatory demyelinating polyradiculoneuropathy. Outcome measures had to include one of the following: a disability score, the Medical Research Council sum score, electrophysiological data or walking distance. Studies which reported the frequency of adverse effects were used to assess the safety of treatment. DATA COLLECTION AND ANALYSIS: Two reviewers independently reviewed literature searches to identify potentially relevant trials, scored their quality and extracted data independently. For dichotomous data, we calculated relative risks, and for continuous data, effect sizes (for definition see statistical analysis section) and weighted pooled effect sizes. Statistical uncertainty was expressed in 95% confidence intervals. Sensitivity analysis excluding studies with quality scores below A 0.50 and below B 0.75 was planned but not performed as all studies had quality scores above 0.75. MAIN RESULTS: Six randomised controlled trials were considered eligible including 170 patients. Four studies on 113 patients compared intravenous immunoglobulin against placebo. One trial with 17 patients compared intravenous immunoglobulin with plasma exchange in a cross-over design and one trial compared intravenous immunoglobulin with prednisolone in 32 patients. A significantly higher proportion of patients improved in disability within one month after the onset of intravenous immunoglobulin treatment as compared with placebo (relative risk 3.17, 95% confidence interval 1.74 to 5.75). Whether all these improvements are equally clinically relevant cannot be deduced from this analysis because each trial used a different disability scale with a unique definition of a significant improvement. To overcome this problem an attempt was made to transform the various disability scales to the modified Rankin score. In three trials including 87 patients this transformation could be carried out. A significantly higher proportion of patients improved one point after intravenous immunoglobulin treatment compared to placebo (relative risk 2.47, 95% confidence interval 1.02 to 6.01). The effect size for change of mean disability score at six weeks comparing intravenous immunoglobulin with plasma exchange revealed no difference between the two therapies (effect size -0.07, 95% confidence interval -0.76 to 0.63.) The proportion of patients with a significant improvement did not differ significantly between prednisolone and intravenous immunoglobulin (relative risk of 0.91 (95% CI 0.50 to 1.68). Also, no difference in mean improvement on the disability scale was found at two weeks (effect size -0.12, 95% confidence interval -0.68 to 0.45) or six weeks (effect size -0.07, 95% confidence interval -0.63 to 0.50) between prednisolone and intravenous immunoglobulin. There were no statistically significant differences in frequencies of side effects between the three types of treatment. REVIEWER'S CONCLUSIONS: The evidence from randomised controlled trials shows that intravenous immunoglobulin improves disability for at least two to six weeks compared with placebo, with a number needed to treat of three. During this period it has similar efficacy to plasma exchange and oral prednisolone. Since intravenous immunoglobulin, plasma exchange and prednisolone seem to be equally effective, it is currently uncertain which of these treatments should be the first choice. Cost, side effects, duration of treatment, dependency on regular hospital visits and ease of administration all have to be considered before such a decision can be made.

Guillain Barré syndrome.

Guillain Barré syndrome is one of the best examples of a post infectious immune disease and offers insights into the mechanism of tissue damage in other more common autoimmune diseases. Controlled epidemiological studies have linked it to infection with Campylobacter jejuni in addition to other viruses including cytomegalovirus and Epstein Barr virus. The syndrome includes several pathological subtypes, of which the most common is a multifocal demyelinating disorder of the peripheral nerves in close association with macrophages. Evidence from histological examination of peripheral nerve biopsy and postmortem samples suggests that both cell mediated and humoral mechanisms are involved in the pathogenesis. Immunological studies suggest that at least one third of patients have antibodies against nerve gangliosides, which in some cases also react with constituents of the liposaccharide of C jejuni. In the Miller Fisher variant of the disease, these antiganglioside antibodies have been shown to produce neuromuscular block, and may in part explain the clinical signs of that disorder. Treatment with both intravenous immunoglobulin and plasma exchange reduces the time taken for recovery to occur, although mortality remains around 8%, with about 20% of patients remaining disabled.

Limb girdle and facial weakness in female carriers of X-linked myotubular myopathy mutations.

Although X-linked myotubular myopathy (XLMTM) is a recessive disorder, heterozygous female carriers of MTM1 mutations may present with limb girdle and facial weakness. It is proposed that manifesting heterozygote females with XLMTM have a skewed pattern of X-chromosome inactivation. However, skewed X-chromosome inactivation was not detected in either the lymphocyte or muscle DNA of a woman who presented with limb girdle/facial weakness and was found to be heterozygous for the R224X mutation.

Unusual T cell receptor phenotype V gene usage of gamma delta T cells in a line derived from the peripheral nerve of a patient with Guillain-Barré syndrome.

Guillain-Barré syndrome is considered to be an immune mediated disorder but the relative role of T cells and antibodies in its pathogenesis is unclear. As gut infection with Campylobacter jejuni is the most common antecedent infection it is possible that gut derived T lymphocytes might play a part in the development of the syndrome. The T cell receptor phenotype (TCR) of a nerve gamma delta T cell line obtained from a sural nerve biopsy taken from a patient with a demyelinating form of GBS was determined using polymerase chain reaction (PCR) and flow cytometry (FACS). This TCR was compared with the phenotype preferentially expressed in the peripheral blood of the same patient. The T cell nerve line was found to express V gamma 8/delta 1 which represents an unusual T cell subset normally found on lymphocytes resident in epithelial tissue such as the gut. The peripheral blood gamma delta T lymphocytes from the patient were of the V gamma 9/delta 2 subset, which is the phenotype predominantly expressed in the peripheral blood of healthy subjects. In conclusion, the presence of this unusual population of V gamma 8/delta 1(+) lymphocytes in nerve would be consistent with a pathogenetic role for gut associated lymphocytes in the pathogenesis of Guillain-Barré syndrome associated with C jejuni.

Giant cell arteritis of the cervical radicular vessels presenting with diaphragmatic weakness.

The clinical and histopathological details of a patient who succumbed to giant cell arteritis (GCA) of the cervical radicular vessels are described. The initial clinical presentation, with diaphragmatic weakness, has not previously been reported. Normal inflammatory indices and the unusual presentation prevented diagnosis during life, but GCA should be considered in the differential diagnosis of any unexplained neuropathic or radiculopathic syndrome, as corticosteroid therapy may lead to recovery. This is the first account of the pathological findings in cervical radiculopathy associated with GCA.