Intravenous IgG in Guillain-Barre syndrome

<it>Same short term benefit as plasma exchange but easier to administer</it>

The commonest misdiagnosis of Guillain-Barre syndrome by the doctor of first contact is hysteria. This is understandable when most doctors have not seen a case since medical school. However, the syndrome is neither rare nor trivial. With an incidence of one or two cases per 100 000 population per year, new cases are about half as common as new cases of multiple sclerosis—a disease confined to the central nervous system as closely as Guillain-Barre syndrome is restricted to the peripheral nervous system. A quarter of adult patients require artificial ventilation, 10% die as a result of complications of the disease, and 10% are left with such severe disability that they cannot walk unaided a year later.1

The pathological process underlying Guillain-Barre syndrome is heterogeneous. Most patients have an acute multifocal lymphocytic infiltration in their peripheral nerves and spinal roots causing primary demyelination, which will recover quickly. Severely affected patients usually have additional axonal degeneration, which causes delayed and often incomplete recovery. About 10% of patients have an acute motor, or motor and sensory, axonal neuropathy in which macrophages invade the axons, especially in the spinal roots.2 3 Both types of Guillain-Barre syndrome are thought to be due to an autoimmune response triggered by a preceding infection. Campylobacter jejuni is the commonest recognised culprit and is more likely to be followed by a severe form of the disease with axonal degeneration.4 The proposal that glycolipids, especially ganglioside GM1, in the bacterial cell wall induce an immune response that cross reacts with myelin or axonal antigens is not proved. Consequently the pathogenesis of Guillain-Barre syndrome remains uncertain, the diagnosis clinical, and treatment empirical.

Fortunately, evidence for effective treatment is available. The use of plasma exchange has been endorsed by a trial in which 122 patients randomised to receive this treatment began to walk without aid in a median of 53 days compared with 85 days in a similar number given supportive care alone.5 This evidence was weakened by the open nature of the study but confirmed by a second, similarly large and open, randomised study with an almost identical outcome.6

Plasma exchange is a formidable undertaking in patients with the autonomic instability and nosocomial infections that commonly occur in Guillain-Barre syndrome. Consequently, a comparative randomised trial in which patients treated with intravenous IgG recovered as fast as those treated with plasma exchange was welcome news.7 A larger international trial, which confirmed that plasma exchange and IgG have similar efficacy. Combined treatment with plasma exchange followed by IgG conferred a slight but not clinically significant advantage compared with either treatment alone.8

Although the use of any human blood product must carry theoretical risks of transmitting infection, the safety record of most preparations of IgG has been excellent: serious side effects (anaphylaxis) are very rare; and minor, spontaneously reversible side effects (including meningism, nausea, and malaise) occur in less than 5% of patients. IgG should be avoided in patients with known IgA deficiency, in whom anaphylaxis is more common, and in the presence of renal failure, which may be exacerbated. On grounds of equivalent efficacy, similar cost, greater convenience, and ease of administration, intravenous IgG should now be the treatment of choice for patients with severe Guillain-Barre syndrome during the first two weeks after the start of neuropathic symptoms.

Before the advent of immunoglobulins, a randomised double blind placebo controlled trial had found that corticosteroids were not helpful,9 but a cohort of patients treated with intravenous methylprednisolone as well as IgG recovered faster than a historical control group.10 This result is being checked with a further controlled trial, and at present I do not advocate using corticosteroids.

All the substantial controlled trials so far undertaken have been confined to adults with Guillain-Barre syndrome. In a small open controlled trial, nine children treated with intravenous IgG 1g/kg daily for two days recovered more quickly than children treated with supportive care alone.11 A retrospective study of 175 children aged between 11 months and 18 years confirms general experience that the disease has a more benign course in children.12 Only 16% of child patients required artificial ventilation, and the median delay to freedom of symptoms was 66 days. Of the 106 patients with follow up information, 98 (92%) were free of symptoms at least six months later, and all could walk unaided. Analysis of the outcome, taking into account the maximum disability, suggested that early treatment with IgG or, to a lesser extent, corticosteroids reduced the time to start of recovery and to freedom from symptoms. These conclusions are inevitably weakened by the retrospective study design, which risks incomplete case ascertainment and variable quality of data, and by the high proportion (39%) of patients lost to follow up. Nevertheless, this report based on a large number of cases is in line with the evidence in adults that early severe Guillain-Barre syndrome responds to intravenous IgG.

The use of intravenous IgG in Guillain-Barre syndrome is no substitute for rapid diagnosis and excellent general medical care, nursing, and physiotherapy. Every general practitioner and casualty officer must be able to recognise the early signs of acute neuromuscular paralysis, not easy when the reflexes may still be preserved in the first hours of the illness. Every medical admissions team should to be able to measure vital capacity repeatedly. This means that all wards should have hand held vital capacity measuring machines, which are now quite cheap, instead of relying on peak expiratory flow monitoring devices, which provide inadequate measures of neuromuscular respiratory failure. In addition most patients should have continuous electrocardiographic monitoring for the life threatening tachyarrhythmias and bradyarrhythmias, which may occur in advance of respiratory failure. Adult patients should receive prophylactic low dose subcutaneous heparin.13

Every ward admitting these patients should take advantage of the visiting and counselling services offered by past patients through the Guillain-Barre Syndrome Support Group. For severely affected patients, early transfer to and management by their regional neuroscience centre are usually appropriate. Earlier diagnosis and improved general medical care should allow emerging immunomodulatory treatments to reduce immediate distress and long term disability.

The Guillain-Barre Syndrome Support Group can be contacted at Lincolnshire County Council Offices, Eastgate, Sleaford, Lincolnshire NG34 7EB (telephone/fax No 01529 304615).

Professor Hughes' department has received funds from Sandoz Pharma to support the trial of intravenous IgG, plasma exchange, and combined treatment in Guillain-Barre syndrome.8