The Changing Concepts of Guillain–Barré Syndrome

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The Changing Concepts of Guillain–Barré Syndrome

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Guillain–Barré syndrome^1,2 is a leading cause of acute paralysis. It occurs worldwide, in patients of all ages and both sexes. The weakness develops in a matter of days, sometimes with frightening rapidity and severity. Thirty percent of patients require treatment in critical care units, where ingenuity and resources are taxed to their maximum, and the stress on the patient and family is enormous. Nonetheless, modern management has reduced the mortality rate from 30 to 3 percent, and 75 percent of patients recover completely in 6 to 12 months.

Guillain–Barré syndrome has traditionally been regarded as a poorly understood immune-mediated attack on the myelin sheath of peripheral nerve, hence the descriptive termacute inflammatory demyelinating polyneuropathy. However, new insights from investigations in the past 10 years have dramatically altered this restricted viewpoint. It is known that in demyelinating Guillain–Barré syndrome the severe inflammation may induce a secondary axonal degeneration — a "bystander" effect.³ Recovery in such instances is more prolonged. In 1986, however, Feasby et al.⁴ described five patients with unusually severe Guillain–Barré syndrome in whom electrophysiologic and pathological studies suggested a primary axonal degeneration, a condition now termed acute motor and sensory axonal neuropathy. Earlier results from northern China in 1979^5,6,7 and more recent clinical, electrophysiologic, and pathological studies by McKhann et al.⁸ in the Chinese patients revealed an acute motor axonal neuropathy in children and young adults, similar to Guillain–Barré syndrome except that, again, there was a primary axonal degeneration,and it affected only the motor fibers. During the past 30 years, similar patients had been described in other countries and regions, including Mexico, Spain, South America, Japan, South Korea, India, and, most recently, North America.⁸ These cases tend to occur in the summer and have been linked to infection with Campylobacter jejuni. C. jejuni is the most common cause of diarrheal illness in developed countries and is ingested in poultry, raw milk, or contaminated water. It must now be regarded as the chief precipitant of Guillain–Barré syndrome. Cytomegalovirus, Epstein–Barr virus, human immunodeficiency virus, and vaccinia are less common causes.⁹ Certain strains of C. jejuni — Pen 19, Lior 11, and Lau 19 and 3/25 — are most likely to precipitate Guillain–Barré syndrome.⁹ Stool cultures may be negative by the time the syndrome appears, usually one to three weeks after the diarrheal illness. Hence, serologic testing for elevated levels of serum IgA, IgM, and IgG, specific to C. jejuni, should be performed, in addition to stool culture.

The report by Rees et al. in this issue of the Journal¹⁰ further clarifies the relations between C. jejuni and Guillain–Barré syndrome. In a prospective study of 96 patients with the syndrome who were identified during one and a half years in England and Wales, 27 (26 percent) had bacteriologic and serologic evidence of preceding C. jejuni infection, as compared with an incidence of 2 percent in household and hospital controls. Patients with the more severe, axonal, form — whether primary or secondary to demyelination — were more likely to have C. jejuni infection. The group with poor outcomes — six patientswho died and seven who were severely disabled — were older and more often were C. jejuni–positive, required ventilatory support, and became bedbound within two days of the onset of neuropathic symptoms. For the C. jejuni–positive patients, the median time to regain the ability to walk was 89 days, as compared with only 45 days for C. jejuni–negative patients.

The C. jejuni story offers new insights into the pathogenesis of Guillain–Barré syndrome.¹¹ The immune mechanism of "molecular mimicry" now seems tenable. Peripheral nerves may share epitopes, or antigenic sites, with C. jejuni; thus, the immune response initially mounted to attack C. jejuni is misdirected to peripheral nerve. Although proof of this theory is still lacking, it is tempting to speculate that since infection with C. jejuni may be associated with either primary demyelinating or primary axonal degeneration, the target epitope may reside in the myelin sheath, the axon, or both. Certain neuronal systemsseem more susceptible in some patients than in others. Thus, a variant of Guillain–Barré syndrome, the Miller Fisher syndrome, has also been linked to C. jejuni.¹⁰ In this syndrome, ophthalmoplegia and sensory ataxia predominate, and there is probably a primary axonal degeneration of cranial-nerve motor axons and peripheral-nerve sensory axons. Future investigations may explain more precisely the recognized variants of Guillain–Barré syndrome: acute inflammatory demyelinating polyneuropathy, acute motor sensory axonal neuropathy, acute motor axonal neuropathy, and Miller Fisher syndrome.

Some have wondered whether the axonal form of Guillain–Barré syndrome is the same as the polyneuropathy of critical illness, an often occult, potentially reversible motor and sensory axonal polyneuropathy confined largely to patients in critical care units. However, critical-illness polyneuropathy occurs as a nonimmune response to severe infection or trauma of virtually any type, including sepsis with what is now termed the systemic inflammatory response syndrome. In sepsis the mechanism is probably a complex disturbance of the systemic microcirculation, in which peripheral nerves suffer impaired perfusion, leading to severe energy deficits and a predominantly distal axonal degeneration.¹²

These changing concepts have practical implications. The identification of only 96 patients with Guillain–Barré syndrome in England and Wales during one and one half years, while 2 percent of hospital or household controls had serum samples positive for C. jejuni, means the chances that Guillain–Barré syndrome will develop after C. jejuni infection must be extremely small. Moreover, C. jejuni infection is usually a relatively benign, self-limiting illness not requiring antibiotic treatment. It spreads chiefly by animal-to-human rather than human-to-human contact. Thus, although public health measures to prevent C.jejuni and other, similar, infections are indicated, investigating and then treating each case of suspected C. jejuni infection with antibiotics simply to prevent the unlikely complication of Guillain–Barré syndrome seems impractical and is still of unproved benefit. If the syndrome does develop, however, a history of diarrheal illness and positive cultures or positive serologic tests for C. jejuni (the results of serologic tests should be available within 48 hours) may signal a potentially more severe axonal disease. This evidence of C. jejuni infection may be the only early warning, since electrophysiologic studies, although valuable in establishing the presence of polyneuropathy, may fail to distinguish axonal from demyelinating disease in the first three weeks.¹³ However, it must be emphasized that C. jejuni in some patients may be associated with a pure demyelinating or a milder axonal neuropathy, with early recovery; even patients with a severe axonal neuropathy may eventually recover.¹⁴ Thus, all patients should receive optimal care, if possible by immediate referral to a tertiary care center. There, investigations, monitoring, and if necessary, intervention by management in a critical care unit can be instituted. Such interventions may include treatment with plasmapheresis or intravenous immune globulin, which may be effective, although perhaps to a lesser degree, against the axonal as well as the demyelinating form of Guillain–Barré syndrome.^9,15

Charles F. Bolton, M.D.
University of Western Ontario
London, ON N6A 4G5, Canada

References

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12. Bolton CF. Critical illness polyneuropathy. In: Thomas PK, Asbury A, eds. Peripheral nerve disorders II. Oxford, England: Butterworth–Heinemann, 1995:262-80.
13. Brown WF. Acute and chronic inflammatory demyelinating neuropathies. In: Brown WF, Bolton CF, eds. Clinical electromyography. 2nd ed. Boston: Butterworth–Heinemann, 1993:533-59.
14. Ho TW, Mishu B, Li CY, et al. Guillain-Barré syndrome in northern China: relationship to Campylobacter jejuni infection and antiglycolipid antibodies. Brain 1995;118:597-605. [Free Full Text]
15. van der Meché FGA, Schmitz PIM, Dutch Guillain-Barré Study Group. A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barré syndrome. N Engl J Med 1992;326:1123-1129. [Abstract]

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