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Biomedical subjects

Richard A C Hughes

Publications and source records attributed to Richard A C Hughes.

16 recordsLinked to original sources
PubMed2006

Pathogenesis of chronic inflammatory demyelinating polyradiculoneuropathy.

The acute lesions of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) consist of endoneurial foci of chemokine and chemokine receptor expression and T cell and macrophage activation. The myelin protein antigens, P2, P0, and PMP22, each induce experimental autoimmune neuritis in rodent models and might be autoantigens in CIDP. The strongest evidence incriminates P0, to which antibodies have been found in 20% of cases. Failure of regulatory T-cell mechanism is thought to underlie persistent or recurrent disease, differentiating CIDP from the acute inflammatory demyelinating polyradiculoneuropathy form of Guillain-Barré syndrome. Corticosteroids, intravenous immunoglobulin and plasma exchange each provide short term benefit but the possible long-term benefits of immunosuppressive drugs have yet to be confirmed in randomised, controlled trials.

Animals↗
PubMed2005

Guillain-Barré syndrome.

Guillain-Barré syndrome consists of at least four subtypes of acute peripheral neuropathy. Major advances have been made in understanding the mechanisms of some of the subtypes. The histological appearance of the acute inflammatory demyelinating polyradiculoneuropathy (AIDP) subtype resembles experimental autoimmune neuritis, which is predominantly caused by T cells directed against peptides from the myelin proteins P0, P2, and PMP22. The role of T-cell-mediated immunity in AIDP remains unclear and there is evidence for the involvement of antibodies and complement. Strong evidence now exists that axonal subtypes of Guillain-Barré syndrome, acute motor axonal neuropathy (AMAN), and acute motor and sensory axonal neuropathy (AMSAN), are caused by antibodies to gangliosides on the axolemma that target macrophages to invade the axon at the node of Ranvier. About a quarter of patients with Guillain-Barré syndrome have had a recent Campylobacter jejuni infection, and axonal forms of the disease are especially common in these people. The lipo-oligosaccharide from the C jejuni bacterial wall contains ganglioside-like structures and its injection into rabbits induces a neuropathy that resembles acute motor axonal neuropathy. Antibodies to GM1, GM1b, GD1a, and GalNac-GD1a are in particular implicated in acute motor axonal neuropathy and, with the exception of GalNacGD1a, in acute motor and sensory axonal neuropathy. The Fisher's syndrome subtype is especially associated with antibodies to GQ1b, and similar cross-reactivity with ganglioside structures in the wall of C jejuni has been discovered. Anti-GQ1b antibodies have been shown to damage the motor nerve terminal in vitro by a complement-mediated mechanism. Results of international randomised trials have shown equivalent efficacy of both plasma exchange and intravenous immunoglobulin, but not corticosteroids, in hastening recovery from Guillain-Barré syndrome. Further research is needed to discover treatments to prevent 20% of patients from being left with persistent and significant disability.

Adult↗
PubMed2005

Supportive care for patients with Guillain-Barré syndrome.

A multidisciplinary consensus group searched MEDLINE from 1966 to May 2003, extracted relevant references, and prepared recommendations on supportive care for Guillain-Barré syndrome. In the absence of randomized controlled trials, we agreed on recommendations by consensus based on observational studies and expert opinion. In the acute phase in bed-bound adult patients, the group recommended the use of heparin and graduated pressure stockings to prevent deep vein thrombosis, monitoring for blood pressure, pulse, autonomic disturbances, and respiratory failure, and the timely institution of artificial ventilation and tracheostomy. Pain management is difficult, but carbamazepine or gabapentin may help. The cautious use of narcotic analgesics may be needed. Disabled patients should be treated by a multidisciplinary rehabilitation team and should receive an assistive exercise program. Persistent fatigue following Guillain-Barré syndrome is common and may be helped by an exercise program. Because of a very small and possibly only theoretical increase in the risk of recurrence following immunization, the need for immunization should be reviewed on an individual basis. More research is needed to identify optimal methods for all aspects of supportive care.

Autonomic Nervous System Diseases↗
PubMed2005

Severity of Guillain-Barré syndrome is associated with Fc gamma Receptor III polymorphisms.

Macrophages and ganglioside-specific IgG are involved in the pathogenesis of Guillain-Barre syndrome (GBS). Leukocyte IgG receptors (Fc gammaR) confer potent cellular effector functions to the specificity of IgG. The efficacy of IgG-mediated cellular inflammatory responses is determined by functional polymorphisms of three Fc gammaR subclasses (Fc gammaRIIa: H131/R131; Fc gammaRIIIa: V158/F158; Fc gammaRIIIb: NA1/NA2). Fc gammaR genotype distributions were determined in a Dutch, and British cohort of GBS patients and controls. In addition, a meta-analysis incorporating all previously published data, encompassing a total of 345 GBS patients and 714 healthy controls, was performed. Results suggest that Fc gammaRIII genotypes may represent mild disease-modifying factors in GBS.

Adult↗
PubMed2005

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.

Adult↗
PubMed2003

Interferon beta 1a for secondary progressive multiple sclerosis.

This non-systematic review identified four randomised trials that have tested the efficacy of interferon beta in secondary progressive multiple sclerosis (SPMS). Two were trials of interferon beta 1a (IFNb1a) and two of interferon beta 1b (IFNb1b). All have shown significant reductions in relapse rates and accumulation of new magnetic resonance imaging (MRI) lesions, but only one trial (of IFNb1b) showed significant slowing of disability progression. Post hoc analyses of these trials suggest that the differences in outcomes might be partly explained by the differences between the trials in the proportions of patients with relapsing disease. In one of the trials of IFNb1a (the SPECTRIMS trial), the hazard ratio for progression in the treated relapsing patients with relapses in the two pre-study years was 0.74 compared to placebo patients with pre-study relapses and 1.01 in the treated patients compared to the placebo patients without pre-study relapses. In the same trial, the treatment effects on MRI parameters were more marked in the patients who had recent pre-study relapses compared with those who had not. These observations have led to the recommendation in national guidelines that prescribing of IFNb in SPMS be limited to those patients who have had disabling relapses in the last 2 years. These conclusions should be reviewed when the full results of all four trials have been published.

Clinical Trials as Topic↗
PubMed2003

Management of chronic inflammatory demyelinating polyradiculoneuropathy.

This review briefly describes current concepts concerning the nosological status, pathogenesis and management of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). CIDP is an uncommon variable disorder of unknown but probably autoimmune aetiology. The commonest form of CIDP causes more or less symmetrical progressive or relapsing weakness affecting proximal and distal muscles. Against this background the review describes the short-term responses to corticosteroids, intravenous immunoglobulin (IVIg) and plasma exchange that have been confirmed in randomised trials. In the absence of better evidence about long-term efficacy, corticosteroids or IVIg are usually favoured because of convenience. Benefit following introduction of azathioprine, cyclophosphamide, cyclosporin, other immunosuppressive agents, and interferon-beta and -alpha has been reported but randomised trials are needed to confirm these benefits. In patients with pure motor CIDP and multifocal motor neuropathy, corticosteroids may cause worsening and IVIg is more likely to be effective. General measures to rehabilitate patients and manage symptoms, including foot drop, weak hands, fatigue and pain, are important.

Anti-Inflammatory Agents↗
PubMed2002

Brain-derived neurotrophic factor in experimental autoimmune neuritis.

Long-term disability in Guillain-Barré syndrome (GBS) is associated with axonal, and some neuronal, degeneration. Brain-derived neurotrophic factor (BDNF) can prevent neuronal death following damage to motor axons and we have therefore examined the ability of BDNF to ameliorate the effects of experimental autoimmune neuritis (EAN), a model of GBS. Treatment of Lewis rats with BDNF (10 mg/kg/day) did not significantly affect the neurological deficit, nor significantly improve survival, motor function or motor innervation. The weight of the urinary bladder was significantly increased in control animals with EAN, but remained similar to normal in animals treated with BDNF. With the exception of a possibly protective effect indicated by bladder weight, this study suggests that BDNF may not provide an effective therapy for GBS, at least in the acute phase of the disease.

Animals↗
PubMed2002

Anti-myelin-associated glycoprotein antibodies alter neurofilament spacing.

Axon calibre is crucial to efficient impulse transmission in the peripheral nervous system. Neurofilament numbers determine gross axonal diameter, but intra-axonal distribution depends on the phosphorylation status of neurofilament sidearms. Myelin-associated glycoprotein (MAG) has been implicated in the signalling cascade controlling neurofilament phosphorylation and hence in the control of axon calibre. In an electron microscopic morphometric study we measured nearest neighbour neurofilament distances (NNND) in the axons of sural nerves from patients with anti-MAG paraproteinaemic neuropathies and compared these with normal human sural nerves and those from patients with Guillain-Barré syndrome or chronic inflammatory demyelinating polyradiculoneuropathy. Axon calibre was similar in all groups. In normal human sural nerves, axonal NNND was correlated with axonal diameter (r = 0.56). In diseased axons this correlation did not exist. The NNND was significantly reduced in demyelinated axons (30.5+/-2.2 nm) and those with widely spaced myelin (28.9+/-1.3 nm) from patients with anti-MAG antibodies compared with normal axons from normal patients (39.8+/- 3.2 nm) or those with demyelinating neuropathy (35.8+/-4.6 nm). This reinforces the hypothesis that MAG is involved in the control of neurofilament spacing through sidearm phosphorylation and demonstrates a MAG-mediated pathogenic effect of the anti-MAG antibody in peripheral nerves.

Adolescent↗