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ABSTRACT: Chronic inflammatory demyelinating polyradiculoneuropathy is a disease causing progressive or relapsing and remitting weakness and numbness. It is probably due to an autoimmune inflammatory process. Immunosuppressive or immunomodulatory drugs would be expected to be beneficial.
We aimed to review systematically the evidence from randomised trials concerning cytotoxic drugs and interferons for chronic inflammatory demyelinating polyradiculoneuropathy.
We searched the Cochrane Neuromuscular Disease Group trials register (searched December 2001), MEDLINE (searched January 1977 to December 2001), EMBASE (January 1980 to December 2001), CINAHL (searched January 1982 to December 2001) and LILACS (searched January 1982 to December 2001). We contacted the authors of the trials identified and other disease experts seeking other published and unpublished trials.
We sought randomised and quasi-randomised trials of all immunosuppressive agents such as azathioprine, cyclophosphamide, methotrexate, cyclosporin A, mycophenolate mofetil, and rituximab and all immunomodulatory agents such as alpha interferon and beta interferon in participants fulfilling standard diagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy.
Two of us independently selected the trials which met our criteria, judged their methodological quality and extracted the data onto specially designed forms. We wanted to measure the change in disability after one year as our primary outcome measure.
We found one parallel group open trial of azathioprine for nine months involving 27 participants and another of interferon beta involving 10 participants in a double blind crossover trial with each treatment period lasting 12 weeks. Neither trial provided our primary outcome measure and neither showed a significant beneficial effect on any of the outcome measures selected by the authors or ourselves in the protocol for this review.
The evidence is inadequate to decide whether azathioprine, interferon beta or any other immunosuppressive drug or interferon is beneficial in chronic inflammatory demyelinating polyradiculoneuropathy.
Cochrane database of systematic reviews (Online) 02/2003; · 5.72 Impact Factor
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ABSTRACT: The detection of an occult tumour in a patient with a suspected paraneoplastic neurological disorder (PND) may be difficult because of the limitations of conventional imaging techniques. [(18)F]fluoro-2-deoxyglucose-PET (FDG-PET) can visualize a small tumour anywhere within the body. We retrospectively reviewed the case notes of 43 unselected patients with suspected PND referred for FDG-PET scanning to determine how useful this technique was when conventional imaging was negative. All patients had undergone standard radiological investigations and bronchoscopy (where appropriate) prior to PET scanning. There were discrete areas of hypermetabolism suggestive of malignancy (positive) in 16 patients (37%). A tissue diagnosis of cancer was subsequently made in seven patients (two at post-mortem), further radiological studies were suggestive of cancer in one patient, one patient subsequently presented with a metastatic deposit which was biopsied, and four patients died shortly afterwards without a post-mortem. In three patients, subsequent investigations were negative for cancer. Serum anti-neuronal antibodies were present in 43% and CSF oligoclonal bands were present in 46% of patients with positive PET scans compared with 16 and 26%, respectively, in PET-negative patients, but this was not significant. Only one patient with a negative scan has been diagnosed subsequently as having malignancy on prolonged follow-up. These findings confirm that FDG-PET scanning is a useful technique in the detection of small tumours in patients with suspected PND. False positives and false negatives do occur, but at a sufficiently low frequency to justify the clinical usefulness of this technique.
Brain 12/2001; 124(Pt 11):2223-31. · 9.46 Impact Factor
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ABSTRACT: To investigate whether antibodies are pathogenic in Guillain-Barré syndrome (GBS), we injected pre-treatment serum from 11 GBS patients intraperitoneally into rats in which the blood-nerve barrier had been opened by induction of mild adoptive transfer experimental autoimmune neuritis. There was no significant clinical, neurophysiological or pathological difference between rats receiving GBS serum compared with those receiving control serum, except that GBS serum caused minor excess weight loss. Murine monoclonal antibody to Campylobacter jejuni and gangliosides also did not exacerbate disease. This experiment failed to show antibody-mediated disease exacerbation and so does not support an antibody-mediated mechanism in GBS.
Journal of Neuroimmunology 11/2001; 119(2):306-16. · 2.96 Impact Factor
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R A Hughes
The Lancet 06/2001; 357(9267):1465. · 38.28 Impact Factor
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R D Hadden,
H Karch,
H P Hartung,
J Zielasek,
B Weissbrich,
J Schubert,
A Weishaupt,
D R Cornblath,
A V Swan, R A Hughes,
K V Toyka
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ABSTRACT: To test the hypothesis that different preceding infections influence the neurophysiologic classification and clinical features of Guillain-Barré syndrome (GBS).
We tested pretreatment sera, 7 +/- 3 (mean +/- SD) days from onset, from 229 patients with GBS in a multicenter trial of plasma exchange and immunoglobulin, for serological markers of infection, adhesion molecules, and cytokine receptors, and compared these with neurophysiologic and clinical features.
Recent infection by Campylobacter jejuni was found in 53 patients (23%), cytomegalovirus in 19 (8%), and Epstein-Barr virus in four (2%). Patients with C. jejuni infection were more likely than others to have neurophysiologic criteria of axonal neuropathy or inexcitable nerves, antiganglioside GM(1) antibodies, pure motor GBS, lower CSF protein, and worse outcome. Patients with cytomegalovirus infection were younger and more likely than others to have raised serum concentrations of molecules important in T lymphocyte activation and migration, soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble leukocyte selectin, and soluble interleukin-2 receptor (sIL-2R). Concentrations of sICAM-1 and soluble tumor necrosis factor receptor were higher in patients with inexcitable nerves than those with demyelinating neurophysiology. Logistic regression analysis showed death or inability to walk unaided at 48 weeks were associated with diarrhea, inexcitable nerves, severe arm weakness, age over 50, raised sIL-2R concentration and absence of immunoglobulin (Ig) M antiganglioside GM(1) antibodies.
Subtypes of GBS defined by preceding infections were only approximately associated with different patterns of clinical, neurophysiologic, and immunologic features. A single infectious agent caused more than one type of pathology in GBS, implying interaction with additional host factors. Most patients had no identified infection.
Neurology 04/2001; 56(6):758-65. · 8.31 Impact Factor
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ABSTRACT: Guillain-Barré syndrome is a potentially serious, acute, paralysing, probably autoimmune disease caused by inflammation of the peripheral nerves. Recovery has been shown to be speeded by plasma exchange which replaces the patient's own plasma with a plasma substitute. Intravenous immunoglobulin purified from donated blood is beneficial in other autoimmune diseases and is easier to administer.
To determine the efficacy of intravenous immunoglobulin in comparison with no treatment or other treatments for treating Guillain-Barré syndrome and to determine the most efficacious dose.
Search of the Cochrane Neuromuscular Disease Group register using Guillain-Barré syndrome and acute polyradiculoneuritis as the search terms, bibliographies of trials and contact with their authors and other experts.
Randomised and quasi-randomised trials.
Two reviewers examined the titles and abstracts of all the papers retrieved by the search, extracted the data onto forms designed for this review, and independently assessed the quality of the trials.
The only trial comparing intravenous immunoglobulin with supportive treatment was inadequate to establish its value. Another Cochrane systematic review has shown that plasma exchange (PE) hastens recovery. Plasma exchange has become the gold standard against which other treatments need to be compared. We found three randomised trials that compared intravenous immunoglobulin with PE. We were able to combine the results of the two largest trials in a metaanalysis involving 398 patients. The primary outcome measure in this review was the change in a 7 grade disability scale four weeks after randomisation. The weighted mean difference of this measure was not significant, being only 0.11 (95% CI -0.14 to 0.37) of a disability grade more improvement in the intravenous immunoglobulin group than the PE group. There were also no significant differences in other outcome measures, including time to walk unaided, mortality, and proportion of patients unable to walk without aid after a year but some of these outcome measures were only available for one trial. We also reviewed one trial involving 249 patients which compared PE followed by intravenous immunoglobulin with PE alone and another involving 37 patients which compared immunoabsorption followed by intravenous immunoglobulin with immunoabsorption alone. Neither revealed any significant differences between the regimens with and without intravenous immunoglobulin. We did not discover any dose ranging studies of intravenous immunoglobulin except for one that is ongoing.
There are no adequate trials to determine whether intravenous immunoglobulin is more beneficial than placebo. Intravenous immunoglobulin and plasma exchange have a similar ability to speed the recovery from Guillain-Barré syndrome. Giving intravenous immunoglobulin after plasma exchange is not significantly better than plasma exchange alone. Randomised trials are needed to decide whether intravenous immunoglobulin helps in mild Guillain-Barré syndrome or in disease which has lasted more than two weeks. Randomised trials also need to establish the optimal dose.
Cochrane database of systematic reviews (Online) 02/2001; · 5.72 Impact Factor
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ABSTRACT: This study aimed to determine the usefulness of sural nerve biopsy in neurological practice.
The first prospective study of sural nerve biopsy in 50 consecutive patients was undertaken. The investigating neurologist declared the prebiopsy diagnosis and management plan and after 3 months an independent neurologist evaluated the contribution of the biopsy to diagnosis and management. An independent audit officer sought information from the patient about the adverse effects and value of the biopsy after 6 weeks and 6 months.
In seven cases the nerve biopsy changed the diagnosis, in 35 cases the biopsy confirmed the suspected diagnosis, and in eight cases the biopsy was non-contributory. The biopsy either changed or was helpful in guiding patient management in 60%, especially those with demyelinating neuropathy and multiple mononeuropathy. Seven patients reported having had infection and 10 reported increased pain at the biopsy site 6 months later.
In a consecutive series of 50 cases, sural nerve biopsy altered the diagnosis in 14%, affected management in 60%, and caused persistent increased pain at the biopsy site in 33%.
Journal of Neurology Neurosurgery & Psychiatry 11/2000; 69(4):442-6. · 4.76 Impact Factor
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ABSTRACT: Brain-derived neurotrophic factor (BDNF) has the theoretical potential to protect neurones from axonal degeneration. The objective of this study was to discover whether brain-derived neurotrophic factor is safe in Guillain-Barré syndrome, and to make preliminary observations of its efficacy. This was a parallel group randomized controlled trial of subcutaneous brain-derived neurotrophic factor 25 microg/kg daily compared with placebo for up to 24 weeks or until patients could walk without aid. Six patients received brain-derived neurotrophic factor, of whom three had serious adverse events including one death. Four patients received placebo, of whom two had serious adverse events including one death. The rate and extent of recovery were similar in the two groups. This pilot study did not detect any serious adverse events attributed to brain-derived neurotrophic factor treatment.
European Journal of Neurology 08/2000; 7(4):423-6. · 3.69 Impact Factor
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ABSTRACT: An experimental model of inflammatory radiculoneuropathy is induced by immunising rats with peripheral myelin protein 22 (PMP22). We have investigated whether PMP22 may be important in inducing human inflammatory neuropathy. We examined sera of patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), other neuropathies (ONP) and normal controls for IgM and IgG antibodies against PMP22 by ELISA (against synthetic PMP22 extracellular peptide fragments) and Western blot (against cauda equina). Antibodies were detected by both methods in 52% of patients with GBS, 35% with CIDP, 3% with ONP and no normal controls. We conclude that an immune response against PMP22 may play a role in the pathogenesis of the inflammatory neuropathies.
Journal of Neuroimmunology 06/2000; 104(2):139-46. · 2.96 Impact Factor
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B Sharrack, R A Hughes,
R W Morris,
S Soudain,
O Wade-Jones,
D Barnes,
P Brown,
T Britton,
D A Francis,
G D Perkin,
P Rudge,
M Swash,
H A Katifi,
S Farmer,
J P Frankel
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ABSTRACT: We investigated the effect of oral and intravenous methylprednisolone treatment on subsequent relapse rate in patients with multiple sclerosis. Following a double blind trial designed to compare the effect of oral and intravenous methylprednisolone treatment on promoting recovery from acute relapses of multiple sclerosis, 80 patients were followed for two years with six-monthly assessments during which all subsequent relapses were recorded. The annual relapse rate was slightly higher in the oral compared with the intravenous methylprednisolone-treated patients (1.06 vs. 0.78), but the adjusted difference between the two groups was not statistically significant (0.18; 95% CI -0.19 to 0.55, P=0.3). The time to onset and the severity of the first relapse after treatment, the number of relapse free patients at the end of the follow-up period, and the severity of the relapses during the follow-up period were similar in the two groups. This trial did not show a statistically significant difference in relapse rate during the first two years following oral compared with intravenous methylprednisolone treatment.
Journal of the Neurological Sciences 03/2000; 173(1):73-7. · 2.35 Impact Factor
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ABSTRACT: Recent neurophysiological and pathological studies have led to a reclassification of the diseases that underlie Guillain-Barré syndrome (GBS) into acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute motor and sensory axonal neuropathy (AMSAN) and acute motor axonal neuropathy (AMAN). The Fisher syndrome of ophthalmoplegia, ataxia and areflexia is the most striking of several related conditions. Significant antecedent events include Campylobacter jejuni (4-66%), cytomegalovirus (5-15%), Epstein-Barr virus (2-10%), and Mycoplasma pneumoniae (1-5%) infections. These infections are not uniquely associated with any clinical subtype but severe axonal degeneration is more common following C. jejuni and severe sensory impairment following cytomegalovirus. Strong evidence supports an important role for antibodies to gangliosides in pathogenesis. In particular antibodies to ganglioside GM1 are present in 14-50% of patients with GBS, and are more common in cases with severe axonal degeneration associated with any subtype. Antibodies to ganglioside GQ1b are very closely associated with Fisher syndrome, its formes frustes and related syndromes. Ganglioside-like epitopes exist in the bacterial wall of C. jejuni. Infection by this and other organisms triggers an antibody response in patients with GBS but not in those with uncomplicated enteritis. The development of GBS is likely to be a consequence of special properties of the infecting organism, since some strains such as Penner 0:19 and 0:41 are particularly associated with GBS but not with enteritis. It is also likely to be a consequence of the immunogenetic background of the patient since few patients develop GBS after infection even with one of these strains. Attempts to match the subtypes of GBS to the fine specificity of anti-ganglioside antibodies and to functional effects in experimental models continue but have not yet fully explained the pathogenesis. T cells are also involved in the pathogenesis of most or perhaps all forms of GBS. T cell responses to any of three myelin proteins, P2, PO and PMP22, are sufficient to induce experimental autoimmune neuritis. Activated T cells are present in the circulation in the acute stage, up-regulate matrix metalloproteinases, cross the blood-nerve barrier and encounter their cognate antigens. Identification of the specificity of these T cell responses is still at a preliminary stage. The invasion of intact myelin sheaths by activated macrophages is difficult to explain according to a purely T cell mediated mechanism. The different patterns of GBS are probably due to the diverse interplay between antibodies and T cells of differing specificities.
Journal of Neuroimmunology 01/2000; 100(1-2):74-97. · 2.96 Impact Factor
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ABSTRACT: Experimental models have suggested potential new treatments for human inflammatory neuropathy, but current practice is largely based on empirical trials. Evidence from randomized trials supports the use of intravenous immunoglobulin in Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy with conduction block (MMNCB). In Guillain-Barré syndrome and CIDP intravenous immunoglobulin is equivalent to but more convenient than plasma exchange. In MMNCB adequate comparative studies of intravenous immunoglobulin and plasma exchange have not been performed. Corticosteroid treatment is beneficial in CIDP, but not in Guillain-Barré syndrome and may worsen MMNCB. More randomized trials and systematic reviews are needed to improve the evidence base for clinical practice.
Current Opinion in Neurology 11/1999; 12(5):573-9. · 4.94 Impact Factor
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ABSTRACT: A 43-year-old woman is reported who developed acute and later chronic graft-versus-host disease following an unrelated donor bone marrow transplantation for chronic myeloid leukaemia. Four years later, she developed a sensory multiple mononeuropathy with biopsy features of chronic vasculitis. This is the first report of vasculitic neuropathy in association with graft-versus-host disease.
Journal of the Neurological Sciences 10/1999; 168(1):68-70. · 2.35 Impact Factor
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ABSTRACT: A postal survey showed that the majority of 49 leading international neurologists involved with multiple sclerosis research felt that currently existing outcome measures for this illness were inadequate, and that there was a need for a new measure which should be patient orientated, multidimensional, and not biased towards any particular disability. The Guy's Neurological Disability Scale (GNDS) was subsequently devised as a simple and user-friendly clinical disability scale capable of embracing the whole range of disabilities which could be encountered in the course of multiple sclerosis. It has 12 separate categories which include cognition, mood, vision, speech, swallowing, upper limb function, lower limb function, bladder function, bowel function, sexual function, fatigue, and 'others'. The GNDS was found to be acceptable to neurologists and patients, reliable, responsive, and valid as a measure of disability. The scale was also found to be valid when applied by non-neurologists, over the phone, or via a postal questionnaire.
Multiple Sclerosis 09/1999; 5(4):223-33. · 4.26 Impact Factor
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N Tubridy,
P O Behan,
R Capildeo,
A Chaudhuri,
R Forbes,
C P Hawkins, R A Hughes,
J Palace,
B Sharrack,
R Swingler,
C Young,
I F Moseley,
D G MacManus,
S Donoghue,
D H Miller
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ABSTRACT: To determine the effect of humanized monoclonal antibody against alpha4 integrin (reactive with alpha4beta1 integrin or very-late antigen-4) on MRI lesion activity in MS.
A randomized, double-blind, placebo-controlled trial in 72 patients with active relapsing-remitting and secondary progressive MS was performed. Each patient received two IV infusions of anti-alpha4 integrin antibody (natalizumab; Antegren) or placebo 4 weeks apart and was followed up for 24 weeks with serial MRI and clinical assessment.
The treated group exhibited significantly fewer new active lesions (mean 1.8 versus 3.6 per patient) and new enhancing lesions (mean 1.6 versus 3.3 per patient) than the placebo group over the first 12 weeks. There was no significant difference in the number of new active or new enhancing lesions in the second 12 weeks of the study. The number of baseline-enhancing lesions (i.e., lesions that enhanced on the baseline scan) that continued to enhance 4 weeks following the first treatment was not significantly different between the two groups. The number of patients with acute MS exacerbations was not significantly different in the two groups during the first 12 weeks (9 in the treated group versus 10 in placebo) but was higher in the treatment group in the second 12 weeks (14 versus 3; p = 0.005). The study was not, however, designed to look definitively at the effect of treatment on relapse rate. Treatment was well tolerated.
Short-term treatment with monoclonal antibody against alpha4 integrin results in a significant reduction in the number of new active lesions on MRI. Further studies will be required to determine the longer term effect of this treatment on MRI and clinical outcomes.
Neurology 09/1999; 53(3):466-72. · 8.31 Impact Factor
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ABSTRACT: Monoclonal antibodies reactive with the HNK-1 epitope of myelin-associated glycoprotein (MAG) and the sulphate-3-glucuronyl paragloboside (SGPG)-like glycolipids are often found in the serum of patients with IgM paraprotein-associated demyelinating neuropathy. The presence of such antibodies in patients with chronic polyneuropathy has recently been associated with evidence of active cytomegalovirus (CMV) infection by the polymerase chain reaction. We wished to test these findings and examined sera from patients with MAG-reactive or MAG-nonreactive paraproteinemic neuropathy and patients with paraproteinemia only for the presence of CMV DNA and anti-CMV antibodies. CMV DNA was not detected in sera from any patient group. Furthermore, anti-CMV antibody prevalence was normal and similar in all 3 groups. We therefore report no evidence of an association between CMV infection and anti-MAG/SGPG antibodies associated with paraproteinemic peripheral neuropathy.
Annals of Neurology 09/1999; 46(2):267-70. · 11.09 Impact Factor
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ABSTRACT: To test the safety and efficacy of interferon beta-1a (IFN-beta) in treatment-resistant chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).
Current treatment regimens leave 4% to 30% of patients with CIDP with moderate or severe disability. IFN-beta has been reported as beneficial in one treatment-resistant patient.
Ten consecutive treatment-resistant patients were randomized in a double-blind, crossover design to receive placebo or IFN-beta (3 MIU for 2 weeks and then 6 MIU for 10 weeks) subcutaneously three times weekly, followed by 4 weeks without treatment, and then the opposite treatment for 12 weeks. The primary outcome measure was "clinically important" improvement by specified amounts in any three of eight clinical measures: timed 10-m walk, Ambulation Index, expanded Medical Research Council sum score, nine-hole peg test time, Functional Independence Measure, Hammersmith Motor Ability, a new Guy's Neurological Disability Scale, and the EuroQoL quality-of-life scale. These and motor median nerve conduction studies were measured before and after 12 weeks of each treatment.
Clinically important improvement was observed in one patient while taking IFN-beta and two patients while taking placebo. There was no significant difference between IFN-beta and placebo in the change in any of the individual clinical or neurophysiological measures between the beginning and end of treatment. There were no serious adverse events.
This trial shows that IFN-beta is safe but not efficacious in treatment-resistant CIDP.
Neurology 08/1999; 53(1):57-61. · 8.31 Impact Factor
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Annals of the New York Academy of Sciences 07/1999; 878:658-61. · 3.15 Impact Factor
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ABSTRACT: Although there are now widely accepted diagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) there are few epidemiological data. A prevalence study was performed in the four Thames health regions, population 14 049 850. The prevalence date was 1 January 1995. Data were from a national consultant neurologist surveillance programme and the personal case series of two investigators. A diagnosis of CIDP was made according to definite, probable, possible, or suggestive diagnostic criteria. A wide difference in prevalence rates between the four health regions was noted, probably due to reporting bias. In the South East Thames Region, from which the data were most comprehensive the prevalence for definite and probable cases was 1.00/100 000; the highest total prevalence (if possible and suggestive cases were included) would have been 1.24/100 000. On the prevalence date 13% of patients required aid to walk and 54% were still receiving treatment.
Journal of Neurology Neurosurgery & Psychiatry 06/1999; 66(5):677-80. · 4.76 Impact Factor
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Journal of Neurology 04/1999; 246(3):226. · 3.47 Impact Factor
