Immunemodulation therapies

Plasma exchange

Plasma exchange has been investigated extensively in Guillain-Barre syndrome. It involves exchanging approximately 250 ml/kg of plasma over a period of 10 to 14 days. The principle problems with this approach are its cost and potential for cardiovascular compromise. Intensive monitoring is generally required in view of the latter concern.

We have recently completed a systematic overview of the trials evaluating the role of plasma exchange in Guillain-Barre syndrome ( Lang ef al 1994). Five clinical trials (two large randomized trials with over 200 patients in each, and three smaller trials with about 30 patients) were subjected to a methodological critique. One of the smaller trials was randomized, while the other two used alternate allocation. None of the studies was blinded. Patients, whose ages averaged between 44 and 54 years, were enrolled 1 to 2 weeks after the onset of symptoms. The majority of subjects were unable to walk unassisted on entry into the trials. Total plasma exchange volumes of approximately 200 ml/kg and eight plasma volumes were used in two of the studies; slightly smaller volumes were used in the other three trials. The exchanges were carried out over 1 to 2 weeks. Patient follow-up was for 6 months in one trial and for 1 year in the other four.

Overall, these studies indicated that plasmapheresis hastens recovery and helps to prevent respiratory failure. The median time to walking independently was shortened from 85 to 53 days in the Guillain-Barre Syndrome Study Group trial, and from 111 to 70 days in the French Co-operative trial. Muscle strength was regained more rapidly. For example, the Guillain-Barre Syndrome Study Group found that 59 per cent of treated patients had improved by one grade at 1 month compared with only 39 per cent in the control group (p < 0.01); the motor grading scale used is shown in Table. .. 2. Pooling the trials gave a common odds ratio of 2.49 (95 per cent confidence interval 1.5-4.1, p < 0.0002) for improvement by one grade at 1 month.

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Table 2 Motor grading scale

The French Co-operative trial reported that only 21.4 per cent of their treated patients required ventilatory support if they were randomized prior to developing respiratory failure. This contrasts with the 42.6 per cent that they noted in their control group.

Mortality was unaffected (3 per cent in the Guillain-Barre Syndrome Study Group trial and 6 per cent in the French Co-operative trial). Likewise, long-term disability does not appear to be altered by plasmapheresis. The French Co-operative study found a rate of severe disability of 11 per cent at 1 year. Interestingly, the same trial noted that complete recovery differed significantly between the two arms of the trial at 1 year (60 per cent in the treated group and only 39 per cent in the control patients). Relapse rates did not differ significantly in the two largest trials. With regard to complications, the only significant difference noted was that the patients receiving plasmapheresis in the French Co-operative trial had a higher rate of septicemia (12.8 versus 4.5 per cent).

The French Co-operative trial also compared two different exchange fluids, namely albumin and fresh frozen plasma. No significant differences were noted with respect to the neurological endpoints. However, several patients receiving fresh frozen plasma developed viral hepatitis, and the frequency of incidents (including fevers and skin rashes) was higher in this group. The authors concluded that fresh frozen plasma should not be used as a replacement fluid in view of these associated risks and the lack of any demonstrated benefit over albumin.

Intravenous immunoglobulin

Since plasma exchange requires relatively intense monitoring and specialized equipment and is not universally available, and intravenous immunoglobulin has been found to be beneficial in chronic inflammatory demyelinating polyneuropathy, interest has shifted to this alternative immune-modulation therapy.

Only one trial to date has assessed this treatment in a randomized fashion; 147 patients who were unable to walk 10 m unassisted and whose symptoms had appeared within the previous 2 weeks were randomized to plasma exchange (200-250 ml/kg over 7-14 days) or intravenous immunoglobulin (0.4 g/kg daily for 5 days) in a non-blinded fashion. Patients with a history of a severe allergic reaction to properly matched blood or with a known history of selective IgA deficiency were excluded. The patients were then followed for 6 months. More immunoglobulin-treated patients had improved by at least one motor grade at 1 month than patients who had received plasmapheresis (53 versus 34 per cent; 19 per cent difference with a 95 per cent confidence interval of 3 to 34 per cent). They also noted that at 2 weeks fewer patients were ventilated in the immunoglobulin group (27 per cent versus 42 per cent, p < 0.05). Relapses were similar in the two groups during the follow-up period.

More recently, several small case series have noted an increased relapse rate with intravenous immunoglobulin. One reported a relapse in five out of seven patients, while another noted deterioration in almost half of the 15 patients treated. Further randomized trials comparing intravenous immunoglobulin with plasma exchange are in progress.

Corticosteroids

For many years, corticosteroids were believed to be beneficial in Guillain-Barre syndrome. Numerous cases series suggested that they hastened recovery and improved overall outcome. However, two randomized, controlled trials assessed this question and arrived at a different conclusion. The first trial randomized patients with an acute neuropathy that was not secondary to a metabolic cause to either high-dose oral prednisolone or placebo for 1 week. Throughout the follow-up period of 1 year, a trend towards greater improvement was found in the placebo group, and this reached statistical significance at 3 months for patients who entered the trial within 1 week of the onset of weakness (2.5 grades of improvement in the placebo group versus 0.9 grades in the treated patients). The second trial was larger, randomizing 242 patients with Guillain-Barre syndrome within the first 2 weeks of the illness to either 500 mg of solumedrol (methylprednisolone) intravenously for 5 days or placebo. No significant differences in outcome were noted.

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