It is an honor for me to be invited to serve on the medical advisory board of the Guillain-Barré Syndrome Foundation International and to have an opportunity to write an article for this issue of the communicator. Over recent years I have been closely involved in the medical advisory board of the UK sister organization, the Guillain-Barré Syndrome support group and we all welcome the international effort that is afoot to improve the outcome of patients affected by this illness. I am particularly interested in understanding the cause of GBS, through research into basic pathophysiological mechanisms and have developed a special interest in the antibody responses to verve carbohydrate antigens. These carbohydrate structures are most commonly found on glycolipids. Glycolipids, which when sialylated are termed gangliosides, are a large family of sphingolipids highly enriched in the nervous system where they are involved in diverse biological functions. The flames of this subject were first lit in the mid-1980s around the time I was a visiting fellow in the laboratory of Dr. Richard Quarles at the National Institutes of Health, in Bethesda, Maryland. Dick is one of the founding fathers of this field and laid the cornerstone, the anti-MAG antibody, through meticulous scientific analysis. This led to the discovery of glycolipids and anti-glycolipid antibodies in peripheral nerve disorders. The first scientific paper on this subject in relation to GBS came form Dick’s laboratory, in conjunction with formidable team of GBS research centered around johns Hopkins Hospital in Baltimore. Dick takes no short cuts and always experiments carefully and with intellectual riguor: as such he was a great mentor to me and inspired me to continue working in the field to this day, and for along into the future as I can anticipate. My years spent in the USA were very fruitful and I retain many friends who still work on GBS, some in the USA, and others further afield. We are truly an international community, and this is a great felling.
Since the mid-1980s, there has been remarkable progress in our understanding of the clinical pathophysiology of autoimmune neuropathies that shows no sign of slowing down, particularly the continued identification and analysis of antibodies to gangliosides and related glycolipids in the serum of patients. Antiglycolipid antibodies react with epitopes on the carbohydrate region of glycolipid molecules and can be routinely measured by standard immunoassays. From a clinical diagnostic perspective, they are very useful. For example, in multifocal motor neuropathy, IgM anti-GM1 antibodies are detectable in around 50% of cases. This condition clinically resembles lower motor neuron disease. IgM anti-GD1b antibodies are found in IgM paraproteinaemic neuropathy characterized by profound sensory ataxia. In the anti-myelin associated glycoprotein (anti-MAG) IgM paraproteinaemic neuropathy, antibodies also react with the acidic glycolipids, sulphated glucuronyl paragloboside and its higher lactosaminyl homologue (SGPG and SGLG). Thus a variety of chronic syndromes can be defined by their anti-glycolipid antibody profile and those interested in supporting GBS should not forget the importance of this group of closely related chronic neuropathy syndromes.
In Guillain-Barrp syndrome, anti-GM1, GM1b, GD1a and GalNAc-GD1a antibodies are found in patients with the GBS variant termed acute motor axonal neuropathy (AMAN). These antibodies tend to be IgG class, arise transiently following preceding infections, especially Campylobacter jejuni, and disappear concomitant with clinical recovery. Molecular mimicry (the sharing of antigenic determinants between microbial and host carbohydrate structures) is believed to be the principle mechanism by which they arise. In the acute inflammatory demyelinating polyneuropathy (AIDP) pattern of GBS that is predominant in the USA and in Europe, anti-glycolipid antibodies are less commonly found, although are certainly present in a proportion of cases. GBS occurring in association with Cytomegalovirus infection has been linked with anti-GM2 antibodies. Affected patients have prominent sensory symptoms and cranial nerve involvement. Mycoplasma pneumonia infection preceding GBS is occasionally found in association with anti-GalC antibodies. The significance of finding antibodies to CalC lies in the experimental demonstration that they are capable of inducing morphological and electrophysiological evidence of demyelination. Anti-LM1 and SGPG antibodies have also been reported in AIDP. Understanding this area in more detail remains one of the most pressing areas for research. Are these types of antibodies more frequently present, but hiding for our view, or are they absent in many cases? If the former is the case, we should be looking harder; if the latter is the case, we should be looking elsewhere. In practice both these avenues are being pursued in laboratories around the world.
Miller Fisher syndrome (MFS), or Fisher’s syndrome is the regional variant of GBS that has been of great interest to me since the discovery of anti-GQ1b antibodies. MFS accounts for 5-10% of cases and was first described in 1956 as the clinical triad of ophthalmoplegia, ataxia and areflexia. Since then MFS has evolved as a nosological entity to take into account closely related variants, principally characterized by acute cranial neuropathy with ataxia. Bickerstaff described a now eponymous syndrome in which MFS occurs in conjunction with brain stem involvement, comprising pyramidal tract signs and impaired consciousness. Anti-Go1b ganglioside antibodies were first identified in MFS in a landmark study published in 1992 and this has since been substantiated in many other reports. Anti-GQ1b antibodies are a very sensitive and specific marker ofr MFS and related syndromes characterized by ophthalmoplegia. Anti-GQ1b antibodies are present in over 90% of cases during the acute phase but may disappear rapidly, often being absent during convalescence.
Diagnostic testing for these types of antibodies in GBS should be conducted on serum samples drawn early in the course of the disease. Howerever, it is important to recognize that such testing can never substitute for detailed clinical and electrophysiological analysis that generally yields more useful information to the clinician. Thus much of the data on antiglycolipid antibodies remains research orientated, rather than of primary use in practice. This does not diminish its importance, but simply provides an alternative focus to the debate. It is dangerous to predict the future of research, but I firmly believe that understanding hose anti-glycolipid antibodies injure nerves, and designing strategies for preventing this, will form on of the main areas for future progress in improving the outcome of patients with GBS. Judging by the amount of research taking place worldwide in this area, I am clearly not alone in this view. Organizations such as the GBS Foundation international and GBS support group UK provide a wonderful forum for highlighting this disease and I am very pleased to contribute wherever possible.