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Treatment of Neurological Disorders with Intravenous Immunoglobulins
  1. MICHAEL DONAGHY

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    Treatment of Neurological Disorders with Intravenous Immunoglobulins. Edited by gerard said (Pp 200, £24.95). Published by Martin Dunitz, London, 2000. ISBN 1 85317 758 X.

    Over the past decade the introduction of high dose intravenous immunoglobulin (IvIg) therapy has transformed the treatment of some neuromuscular diseases, particularly multifocal motor neuropathy with conduction block, for which there is no satisfactory alternative therapy. The appearance of this small multiauthor handbook on the use of IvIg in the treatment of neurological disorders is timely. It has been well edited to produce a clear, easily readable, and relatively even style. The tables are useful and well produced. In general, the authors have stuck to the brief of balancing the relative merits of IvIg and conventional therapies for their chosen neurological disorder. However, one or two have used the book as the vehicle for a more general discussion on their chosen disease, accompanied by relatively brief comments on the particular part played by IvIg therapy.

    All regular users of IvIg therapy must be intrigued by the unsolved mystery of its mode of action. The first chapter of this book considers its possible modulatory effects on a myriad of immunological pathways and mechanisms. Initially we all assumed that IvIg contains pooled naturally occurring anti-idiotypes which neutralise the patient's own pathogenic antibodies. Yet pathogenic antibodies have not been identified as the cause of most inflammatory neuropathies which respond to IvIg, and after all this time searching one wonders whether they ever will be. It is surprising that nobody has reported whether IvIg contains natural anti-idiotypes to the well characterised antiacetylcholine receptor antibodies which occur in myasthenia gravis, a disease for which IvIg seems to be effective according to recent trial evidence. This question of anti-idiotypic activity has been explored in the Lambert-Eaton myasthenic syndrome without disclosing obvious evidence of their existence against antibodies to the voltage gated calcium channel. As a frequent observer of the almost magical effect of IvIg in patients with multifocal motor neuropathy, I never fail to be struck by the clear benefit which regularly appears within 48 hours of the first infusion, with improved strength of muscles which may have been weak for years. Surely this rapidity of the effect of IvIg in reversing nerve conduction block is telling us something. It seems too quick to be accounted for by some notion of anti-idiotypic neutralisation of pathogenic antibodies, which would be expected to be firmly bound to the target tissue anyway. Possible explanations are raised in chapter 1, although they are not considered specifically in relation to this astonishingly prompt clinical effect. IvIg can modulate T cell control of the production of cytokines, including tumour necrosis factor-α, which may have the potential to cause nerve conduction block.

    Inevitably much of this book addresses the principal role of IvIg in everyday neurological practice: the treatment of idiopathic demyelinating and conduction block polyneuropathies. In this book, motor neuropathy with conduction block and multifocal sensory demyelinating neuropathy are juxtaposed as rather distinct clinical entities; the second being christened the Lewis-Sumner syndrome. But given the high occurrence of rather non-specific and minor sensory symptoms in patients with multifocal motor neuropathy, and the documentation of sural (sensory) nerve abnormalities in such patients, can we consider these two syndromes as separate, or are they simply peaks within a mountain range? Later on this particular chapter considers whether diabetic proximal neuropathy might benefit from IvIg treatment, given recent evidence of inflammatory infiltrates in cutaneous branches of the femoral nerve, but no clear supporting evidence is presented for this therapeutic notion. The account of the role of IvIg in standard chronic inflammatory sensorimotor demyelinating polyneuropathy is usefully comprehensive. But despite factually correct and well balanced arguments concerning the relative merits of plasma exchange in IvIg in this condition, the book somehow fails to transmit a perspective of when particular clinical circumstances presented by CIDP may merit such therapies, and when to choose each of them. Should plasma exchange be used before IvIg given that it seems effective in about 80% of such patients compared with 65% for IvIg? And if plasma exchange is only partially effective, if it has been given first at least it won't have removed any IvIg administered as ancillary treatment. In Guillain-Barré syndrome the advice, quite rightly, is to give IvIg rather than plasma exchange in patients with potentially severe disease. Yet we remain ignorant of the long term benefit of either of these treatments in a disease which is regarded by many undergraduate textbooks as being relatively benign if you survive the bulbar and respiratory failure. Yet in reality Guillain-Barré syndrome leaves 16% unable to walk at a year, and up to 5% dead, despite IvIg or plasma exchange therapy. It would have been good to hear more on the Baltimore view of whether the long term outcome is better after IvIg than plasma exchange in the acute motor axonal subgroup of Guillain-Barré syndrome. This was an intriguing conclusion of subgroup analysis of the Dutch Guillain-Barré Study Group.

    The other disease-specific chapters of the book address less well established, or minority indications for IvIg. These range from useful discussion on the surprisingly differential benefits of IvIg in the three forms of inflammatory myopathy, to a relatively small trial suggesting partial effectiveness in multiple sclerosis, and largely anecdotal evidence of benefit for the neurological complications of Behçet's syndrome and intractable childhood epilepsy syndromes. Some of these disorders can cause distressingly severe neurological disability. It will be useful to accumulate more data about the possible value of IvIg in treating them whilst acknowledging that it will be difficult to undertake large formal controlled clinical trials. And no doubt matters will be even more difficult in multiple sclerosis, where any future trials of IvIg may have to be in the form of add on therapy to other better established yet only partially effective treatments for the disease, such as β-interferon.

    The final section of this book will be of great help to neurologists. It concerns the rather dry subject of preparation of IvIg, and its safety and tolerability. As any regular IvIg user knows, these questions crop up regularly. The clear and succinct guidance provided by this book is welcome. For instance, tabulation of the characteristics of the 18 commercially available IvIg products compares factors such as the sugars/stabilisers which are used in each; these may be related to some of the side effects. A review of the different methods for inactivating known infectious agents which may be present in the parent plasma pool reminds us that, whereas each method is highly effective, none of the current processes can guarantee total inactivation of infectious viral particles. There is practical advice about how to manage or offset the often encountered, medically trivial, yet none the less irritating, side effects which can occur during infusion. Many patients require regular IvIg for many years, and this volume could have provided more practical guidance on assessing whether it works in an individual patient, whether it works usefully in overcoming disability, and how patients and their families can be trained for domiciliary administration of IvIg.

    A useful little book to keep in your office if you use IvIg regularly to treat neurological diseases. But it leaves untouched some of the most fascinating questions posed by IvIg. Why does it produce its effect so quickly? Why is it so effective in a supposed autoimmune disease, multifocal motor neuropathy, which is worsened by prednisolone therapy? Surely the answers will illuminate the pathogenesis of diseases such as multifocal motor neuropathy.

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